Characterizing osteophyte formation in knee osteoarthritis: application of machine learning quantification of a computerized tomography cohort: Implications for treatment.

BACKGROUND: Osteophytes are commonly used to diagnose and guide knee osteoarthritis (OA) treatment, but their causes are unclear. Although they are not typically the focus of knee arthroplasty surgeons, they can predict case difficulty and length. Furthermore, their extent and location may yield much information about the knee joint status. The aims of this computed tomography (CT)-based study in patients awaiting total or partial knee arthroplasty were to: (1) measure osteophyte volume in anatomical sub-regions and relative change as total volume increases; (2) determine whether medial and/or lateral OA affects osteophyte distribution; and (3) explore relationships between osteophytes and OA severity. METHODS: Data were obtained from 4,928 CT scans. Machine-learning-based imaging analyses enabled osteophyte segmentation and quantification, divided into anatomical regions. Mean three-dimensional joint space narrowing (3D-JSN) was assessed in medial and lateral compartments. A Bayesian model assessed the uniformity of osteophyte distribution. We correlated femoral osteophyte volumes with B-scores, a validated OA status measure. RESULTS: Total tibial (25%) and femoral osteophyte volumes (75%) within each knee correlated strongly (R2 = 0.85). Medial osteophytes (65.3%) were larger than lateral osteophytes (34.6%), with similar proportions in both the femur and tibia. Osteophyte growth was found in all compartments, and as total osteophyte volume increased, the relative distribution of osteophytes between compartments did not markedly change. No evidence of variation was found in the regional distribution of osteophyte volume between knees with medial, lateral, both, or no 3D-JSN in the femur or tibia. There was a direct relationship between osteophyte volume and OA severity. CONCLUSIONS: Osteophyte volume increased in both medial and lateral compartments proportionally with total osteophyte volume, regardless of OA location. The peripheral position of femoral osteophytes does not appear to contribute to load-bearing. This suggests that osteophytic growth represents a 'whole-knee'/global response. This work may have broad applications for knee osteoarthritis, both surgically and non-operatively.

Comparison of 3D quantitative osteoarthritis imaging biomarkers from paired CT and MR images: data from the IMI-APPROACH study.

INTRODUCTION: MRI bone surface area and femoral bone shape (B-score) measures have been employed as quantitative endpoints in DMOAD clinical trials. Computerized Tomography (CT) imaging is more commonly used for 3D visualization of bony anatomy due to its high bone-soft tissue contrast. We aimed to compare CT and MRI assessments of 3D imaging biomarkers. METHODS: We used baseline and 24-month image data from the IMI-APPROACH 2-year prospective cohort study. Femur and tibia were automatically segmented using active appearance models, a machine-learning method, to measure 3D bone shape, area and 3D joint space width (3DJSW). Linear regression was used to test for correlation between measures. Limits of agreement and bias were tested using Bland-Altman analysis. RESULTS: CT-MR pairs of the same knee were available from 434 participants (78% female). B-scores from CT and MR were strongly correlated (CCC = 0.967) with minimal bias of 0.1 (SDD = 0.227). Area measures were also correlated but showed a consistent bias (MR smaller). 3DJSW showed different biases (MR larger) in both lateral and medial compartments. DISCUSSION: The strong correlation and small B-score bias suggests that B-score may be measured reliably using either modality. It is likely that the bone surface identified using MR and CT will be at slightly different positions within the bone/cartilage boundary. The negative bone area bias suggests the MR bone boundary is inside the CT boundary producing smaller areas for MR, consistent with the positive 3DJSW bias. The lateral-medial 3DJSW difference is possibly due to a difference in knee pose during acquisition (extended for CT, flexed for MR). TRIAL REGISTRATION: NCT03883568.

Effect of zoledronic acid with or without methylprednisolone on 3D bone area and bone shape in patients with symptomatic knee osteoarthritis: A post-hoc analysis of the ZAP2 trial.

OBJECTIVE: To evaluate the effect of annual infusions of zoledronic acid (ZA) with or without a single injection of methylprednisolone, compared to placebo, on quantitative magnetic resonance imaging 3-D bone area and bone shape in participants with symptomatic knee osteoarthritis (OA). METHODS: This was a post-hoc analysis of the ZAP2 trial. Active appearance modelling was used to assess bone area (mm2) and femur bone shape (B-score) in 262 participants (mean 61.8 ± 8.0 years, 51% female) at baseline, 6, and 24 months. Radiographic joint space narrowing (JSN) was measured at baseline. An 'OA shape' was defined as a B-score of >1.96. RESULTS: At baseline 65% of participants demonstrated an OA shape. Treatment with ZA plus methylprednisolone but not ZA alone, compared to placebo, was associated with significantly slower expansion in bone area at the medial femoral (-33.9 mm2, 95% confidence interval [CI] -61.8 to -6.0) and lateral femoral (-22.0 mm2, 95%CI -40.7 to -3.4) compartments over 24 months. B-score increased in all groups, with no significant between-group differences. There were significant interactions of JSN (grade 0 vs grade 1-2) and B-score (≤1.96 vs >1.96) with treatment effect on bone area (p < 0.05), such that ZA plus methylprednisolone slowed the expansion of medial and lateral femoral bone area over 24 months in participants with JSN grade 1-2 or a B-score of >1.96. CONCLUSIONS: ZA plus methylprednisolone may retard expansion of bone area over 24 months, but ZA alone may not. Neither ZA with or without methylprednisolone slowed progression of bone shape over 6 or 24 months.

Discovering Associations Between Acoustic Emission and Magnetic Resonance Imaging Biomarkers From 10 Osteoarthritic Knees.

OBJECTIVE: Acoustic emission (AE) sensed from knee joints during weight-bearing movements greatly increases with joint deterioration, but the relationship between AE patterns and specific anatomical damage, as seen for example in magnetic resonance imaging (MRI), is unknown. This knowledge is essential to validate AE biomarkers for the evaluation of knee joints, and forms the objective of this exploratory work to associate knee AE and MRI. METHODS: A novel processing framework is proposed to enable direct correlation between static 3D MRI of knees and their dynamic 1D AE during sit-stand-sit movements. It comprises a method to estimate articular cartilage thickness according to joint angle from knee MRI, and a method to derive statistically representative waveform features according to joint angle from movement and load-dependent knee AE. RESULTS: In 10 subjects diagnosed with knee osteoarthritis, age 55∼79 years and body mass index 25∼35 kg/m2, a strong inverse relationship between knee AE and cartilage thickness in the medial tibiofemoral compartment around the fully standing position was observed. Knees with thinner articular cartilage generated more AE with higher amplitude, greater energy, longer duration, and higher frequencies, in agreement with the assumption of more intense articulation friction under full body weight. CONCLUSION: AE provides promising quantitative biomarkers in knee joint disease. SIGNIFICANCE: These findings provide impetus for the further development of AE as a low-cost non-invasive biomarker modality to improve the management of knee joint disease.

Multivariable Modeling of Biomarker Data From the Phase I Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium.

OBJECTIVE: To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression. METHODS: The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of <0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models). RESULTS: Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832. CONCLUSION: The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

Machine-learning, MRI bone shape and important clinical outcomes in osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVES: Osteoarthritis (OA) structural status is imperfectly classified using radiographic assessment. Statistical shape modelling (SSM), a form of machine-learning, provides precise quantification of a characteristic 3D OA bone shape. We aimed to determine the benefits of this novel measure of OA status for assessing risks of clinically important outcomes. METHODS: The study used 4796 individuals from the Osteoarthritis Initiative cohort. SSM-derived femur bone shape (B-score) was measured from all 9433 baseline knee MRIs. We examined the relationship between B-score, radiographic Kellgren-Lawrence grade (KLG) and current and future pain and function as well as total knee replacement (TKR) up to 8 years. RESULTS: B-score repeatability supported 40 discrete grades. KLG and B-score were both associated with risk of current and future pain, functional limitation and TKR; logistic regression curves were similar. However, each KLG included a wide range of B-scores. For example, for KLG3, risk of pain was 34.4 (95% CI 31.7 to 37.0)%, but B-scores within KLG3 knees ranged from 0 to 6; for B-score 0, risk was 17.0 (16.1 to 17.9)% while for B-score 6, it was 52.1 (48.8 to 55.4)%. For TKR, KLG3 risk was 15.3 (13.3 to 17.3)%; while B-score 0 had negligible risk, B-score 6 risk was 35.6 (31.8 to 39.6)%. Age, sex and body mass index had negligible effects on association between B-score and symptoms. CONCLUSIONS: B-score provides reader-independent quantification using a single time-point, providing unambiguous OA status with defined clinical risks across the whole range of disease including pre-radiographic OA. B-score heralds a step-change in OA stratification for interventions and improved personalised assessment, analogous to the T-score in osteoporosis.

Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial.

Background: MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models. Objective: To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis. Design: 26-week randomized, double-blind, placebo-controlled phase 2a study with a 26-week open-label safety extension substudy. (EudraCT: 2015-003230-26 and 2016-001096-73). Setting: Six European sites. Participants: 244 participants with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS). Intervention: MIV-711, 100 (n = 82) or 200 (n = 81) mg daily, or matched placebo (n = 77). Participants (46 who initially received 200 mg/d and 4 who received placebo) received 200 mg of MIV-711 daily during the extension substudy. Measurements: The primary outcome was change in NRS pain score. The key secondary outcome was change in bone area on magnetic resonance imaging (MRI). Other secondary end points included cartilage thickness on quantitative MRI and type I and II collagen C-telopeptide biomarkers. Outcomes were assessed over 26 weeks. Results: Changes in NRS pain scores with MIV-711 were not statistically significant (placebo, -1.4; MIV-711, 100 mg/d, -1.7; MIV-711, 200 mg/d, -1.5). MIV-711 significantly reduced medial femoral bone area progression (P = 0.002 for 100 mg/d and 0.004 for 200 mg/d) and medial femoral cartilage thinning (P = 0.023 for 100 mg/d and 0.125 for 200 mg/d) versus placebo and substantially reduced bone and cartilage biomarker levels. Nine serious adverse events occurred in 6 participants (1 in the placebo group, 3 in the 100 mg group, and 2 in the 200 mg group); none were considered to be treatment-related. Limitation: The trial was relatively short. Conclusion: MIV-711 was not more effective than placebo for pain, but it significantly reduced bone and cartilage progression with a reassuring safety profile. This treatment may merit further evaluation as a disease-modifying osteoarthritis drug. Primary Funding Source: Medivir.

Very early MRI responses to therapy as a predictor of later radiographic progression in early rheumatoid arthritis.

BACKGROUND: The objective of this study was to evaluate early changes in magnetic resonance imaging (MRI) and clinical disease activity measures as predictors of later structural progression in early rheumatoid arthritis (RA). METHODS: This was a post hoc analysis of data pooled across treatments from a three-arm (tofacitinib monotherapy, tofacitinib with methotrexate [MTX], or MTX monotherapy) trial of MTX-naïve patients with early, active RA. Synovitis, osteitis and erosions were assessed with the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS) and RAMRIQ (automated quantitative RA MRI assessment system; automated RAMRIS) at months 0, 1, 3, 6 and 12. Radiographs were assessed at months 0, 6 and 12, and clinical endpoints were assessed at all timepoints. Univariate and multivariate analyses explored the predictive value of early changes in RAMRIS/RAMRIQ parameters and disease activity measures, with respect to subsequent radiographic progression. RESULTS: Data from 109 patients with a mean RA duration of 0.7 years were included. In univariate analyses, changes in RAMRIS erosions at months 1 and 3 significantly predicted radiographic progression at month 12 (both p <  0.01); changes in RAMRIQ synovitis and osteitis at months 1 and 3 were significant predictors of RAMRIS erosions and radiographic progression at month 12 (all p <  0.01). In subsequent multivariate analyses, RAMRIS erosion change at month 1 (p <  0.05) and RAMRIQ osteitis changes at months 1 and 3 (both p <  0.01) were significant independent predictors of radiographic progression at month 12. Univariate analyses demonstrated that changes in Clinical Disease Activity Index (CDAI) and Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) at months 1 and 3 were not predictive of month 12 radiographic progression. CONCLUSIONS: MRI changes seen as early as 1 month after RA treatment initiation have the potential to better predict long-term radiographic progression than changes in disease activity measures. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01164579 .

Patellofemoral morphology is not related to pain using three-dimensional quantitative analysis in an older population: data from the Osteoarthritis Initiative.

Objectives: Current structural associations of patellofemoral pain (PFP) are based on 2D imaging methodology with inherent measurement uncertainty due to positioning and rotation. This study employed novel technology to create 3D measures of commonly described patellofemoral joint imaging features and compared these features in people with and without PFP in a large cohort. Methods: We compared two groups from the Osteoarthritis Initiative: one with localized PFP and pain on stairs, and a control group with no knee pain; both groups had no radiographic OA. MRI bone surfaces were automatically segmented and aligned using active appearance models. We applied t-tests, logistic regression and linear discriminant analysis to compare 13 imaging features (including patella position, trochlear morphology, facet area and tilt) converted into 3D equivalents, and a measure of overall 3D shape. Results: One hundred and fifteen knees with PFP (mean age 59.7, BMI 27.5 kg/m2, female 58.2%) and 438 without PFP (mean age 63.6, BMI 26.9 kg/m2, female 52.9%) were included. After correction for multiple testing, no statistically significant differences were found between groups for any of the 3D imaging features or their combinations. A statistically significant discrimination was noted for overall 3D shape between genders, confirming the validity of the 3D measures. Conclusion: Challenging current perceptions, no differences in patellofemoral morphology were found between older people with and without PFP using 3D quantitative imaging analysis. Further work is needed to see if these findings are replicated in a younger PFP population.

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

OBJECTIVES: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting. METHODS: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. RESULTS: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks. CONCLUSION: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

Bone Area Provides a Responsive Outcome Measure for Bone Changes in Short-term Knee Osteoarthritis Studies.

OBJECTIVE: To analyze the 3-D bone area from an osteoarthritis (OA) cohort demonstrating no change in cartilage thickness. METHODS: Twenty-seven women with painful medial knee OA had magnetic resonance images at 0, 3, and 6 months. Images were analyzed using active appearance models. RESULTS: At 3 and 6 months, the mean change in medial femoral bone area was 0.34% (95% CI 0.04-0.64) and 0.61% (95% CI 0.32-0.90), respectively. Forty-one percent of the subjects had progression greater than the smallest detectable difference at 6 months. CONCLUSION: In this small cohort at high risk of OA progression, bone area changed at 3 and 6 months when cartilage morphometric measures did not.

Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques.

OBJECTIVES: To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand. METHODS: In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant. RESULTS: In total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were -1.55 (90% CI -2.52 to -0.58) for tofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were -0.63 (-1.58 to 0.31) for tofacitinib + MTX and -0.52 (-1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy. CONCLUSIONS: These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage. TRIAL REGISTRATION NUMBER: NCT01164579.

Osteoarthritic bone marrow lesions almost exclusively colocate with denuded cartilage: a 3D study using data from the Osteoarthritis Initiative.

OBJECTIVES: The aetiology of bone marrow lesions (BMLs) in knee osteoarthritis (OA) is poorly understood. We employed three-dimensional (3D) active appearance modelling (AAM) to study the spatial distribution of BMLs in an OA cohort and compare this with the distribution of denuded cartilage. METHODS: Participants were selected from the Osteoarthritis Initiative progressor cohort with Kellgren-Lawrence scores ≥2, medial joint space narrowing and osteophytes. OA and ligamentous BMLs and articular cartilage were manually segmented. Bone surfaces were automatically segmented by AAM. Cartilage thickness of <0.5 mm was defined as denuded and ≥0.5-1.5 mm as severely damaged. Non-quantitative assessment and 3D population maps were used for analysing the comparative position of BMLs and damaged cartilage. RESULTS: 88 participants were included, 45 men, mean age (SD) was 61.3 (9.9) years and mean body mass index was 31.1 (4.6) kg/m(2). 227 OA and 107 ligamentous BMLs were identified in 86.4% and 73.8% of participants; OA BMLs were larger. Denuded cartilage was predominantly confined to a central region on the medial femur and tibia, and the lateral facet of the trochlear femur. 67% of BMLs were colocated with denuded cartilage and a further 21% with severe cartilage damage. In the remaining 12%, 25/28 were associated with cartilage defects. 74% of all BMLs were directly opposing (kissing) another BML across the joint. CONCLUSIONS: There was an almost exclusive relationship between the location of OA BML and cartilage denudation, which itself had a clear spatial pattern. We propose that OA, ligamentous and traumatic BMLs represent a bone response to abnormal loading.

A novel method for bone area measurement provides new insights into osteoarthritis and its progression.

BACKGROUND: Modern image analysis enables the accurate quantification of knee osteoarthritis (OA) bone using MRI. We hypothesised that three-dimensional changes in bone would be characteristic of OA and provide a responsive measure of progression. METHODS: 1312 participants with radiographic knee OA, and 885 non-OA controls with MRIs at baseline, 1, 2 and 4 years were selected from the NIH Osteoarthritis Initiative. Automated segmentation of all knee bones and calculation of bone area was performed using active appearance models. In a subset of 352 participants, responsiveness of bone area change was compared with change in radiographic joint space width (JSW) and MRI cartilage thickness over a 2-year period. RESULTS: All OA knee compartments showed increased bone area over time compared with non-OA participants: for example, the 4-year percentage change from baseline in medial femur area for OA (95% CI) was 1.87(0.13), non-OA 0.43 (0.07); p<0.0001. Bone area change was more responsive than cartilage thickness or JSW; 2-year SRM for bone area in the medial femur was 0.83, for the most responsive cartilage thickness measure central medial femorotibial composite (cMFTC): 0.38, JSW: 0.35. Almost half of all knees had change greater than smallest detectable difference at 2 years. Body mass index, gender and alignment had only a small effect on the rate of change of bone area. CONCLUSIONS: Changes in bone area discriminated people with OA from controls and was more responsive than the current and impending standards for assessing OA progression. The shape change in OA bone provides a new window on OA pathogenesis and a focus for clinical trials.

Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVES: Bisphosphonates have some reported beneficial effects in treating osteoarthritis (OA). This study examined the effects of bisphosphonate use on symptoms and structural progression of knee OA in participants from the NIH Osteoarthritis Initiative cohort. METHODS: People with typical OA trial entry criteria (KL2/3, minimum joint space width 2.5-5.0 mm and pain ≥4 on a numeric rating scale) were classified as bisphosphonate users (≥3 of the 5 years; n=55) or non-users (no use in the preceding 5 years or during follow-up; n=268). Annual data over 4 years were analysed using linear mixed modelling and generalised estimating equations. RESULTS: Bisphosphonate compliance was 85% at year 1, reducing to 76% by year 4. Numeric rating scale pain scores were significantly reduced among bisphosphonate users at years 2 and 3 (year 3, -0.9 vs -2.2, p=0.004), though not year 4, after adjustment for baseline pain and analgesic use. Differences in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and disability scores did not reach statistical significance at any time point. There was a trend to less joint space narrowing in bisphosphonate users over time (year 4, 0.51 vs 0.29 mm; p=0.06). CONCLUSIONS: Significant reduction in numeric rating scale pain was observed in the first 3 years with bisphosphonate use; diminution of effects by year 4 may reflect reduced compliance. Differences in results obtained using numeric rating scale and WOMAC may reflect different constructs measured by these tools. The beneficial trend on structural progression should be considered in terms of the sample size.

Magnetic resonance imaging-based three-dimensional bone shape of the knee predicts onset of knee osteoarthritis: data from the osteoarthritis initiative.

OBJECTIVE: To examine whether magnetic resonance imaging (MRI)-based 3-dimensional (3-D) bone shape predicts the onset of radiographic knee osteoarthritis (OA). METHODS: We conducted a case-control study using data from the Osteoarthritis Initiative by identifying knees that developed incident tibiofemoral radiographic knee OA (case knees) during followup, and matching them each to 2 random control knees. Using knee MRIs, we performed active appearance modeling of the femur, tibia, and patella and linear discriminant analysis to identify vectors that best classified knees with OA versus those without OA. Vectors were scaled such that -1 and +1 represented the mean non-OA and mean OA shapes, respectively. We examined the relation of 3-D bone shape to incident OA (new-onset Kellgren and Lawrence [K/L] grade ≥2) occurring 12 months later using conditional logistic regression. RESULTS: A total of 178 case knees (incident OA) were matched to 353 control knees. The whole joint (i.e., tibia, femur, and patella) 3-D bone shape vector had the strongest magnitude of effect, with knees in the highest tertile having a 3.0 times higher likelihood of developing incident radiographic knee OA 12 months later compared with those in the lowest tertile (95% confidence interval [95% CI] 1.8-5.0, P < 0.0001). The associations were even stronger among knees that had completely normal radiographs before incidence (K/L grade of 0) (odds ratio 12.5 [95% CI 4.0-39.3]). Bone shape at baseline, often several years before incidence, predicted later OA. CONCLUSION: MRI-based 3-D bone shape predicted the later onset of radiographic OA. Further study is warranted to determine whether such methods can detect treatment effects in trials and provide insight into the pathophysiology of OA development.