M.A. Bowes

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.

A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis

IntroductionBone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA.MethodsA search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring.ResultsIn total 2456 abstracts were screened and 139 papers were included (70 cross-sectional, 71 longitudinal analyses; 116 knee, 15 hip, six hand, two ankle and involved 113 MRI, eight DXA, four CT, eight scintigraphic and eight 2D shape analyses). BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively.ConclusionSubchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target.Systematic reviewPROSPERO registration number: CRD 42013005009

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.

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.

Longitudinal validation of periarticular bone area and 3D shape as biomarkers for knee OA progression? Data from the FNIH OA Biomarkers Consortium

Objective To perform a longitudinal validation study of imaging bone biomarkers of knee osteoarthritis (OA) progression. Methods We undertook a nested case–control study within the Osteoarthritis Initiative in knees (one knee per subject) with a Kellgren and Lawrence grade of 1–3. Cases were defined as knees having the combination of medial tibiofemoral radiographic progression and pain progression at the 24-month, 36-month or 48-month follow-up compared with baseline. Controls (n=406) were eligible knees that did not meet both endpoint criteria and included 200 with neither radiographic nor pain progression, 103 with radiographic progression only and 103 with pain progression only. Bone surfaces in medial and lateral femur, tibia and patella compartments were segmented from MR images using active appearance models. Independent variables of primary interest included change from baseline to 24 months in (1) total area of bone and (2) position on three-dimensional (3D) bone shape vectors that discriminate OA versus non-OA shapes. We assessed the association of bone markers changes over 24 months with progression using logistic regression. Results 24-month changes in bone area and shape in all compartments were greater in cases than controls, with ORs of being a case per 1 SD increase in bone area ranging from 1.28 to 1.71 across compartments, and per 1 SD greater change in 3D shape vectors ranging from 1.22 to 1.64. Bone markers were associated most strongly with radiographic progression and only weakly with pain progression. Conclusions In knees with mild-to-moderate radiographic OA, changes in bone area and shape over 24 months are associated with the combination of radiographic and pain progression over 48 months. This finding of association with longer term clinical outcome underscores their potential for being an efficacy of intervention biomarker in clinical trials.

Measurement and visualisation of focal cartilage thickness change by MRI in a study of knee osteoarthritis using a novel image analysis tool

We describe the application of a novel analysis method that provides detailed maps of changes in cartilage thickness measured from MRI scans for individuals and cohorts of patients together with regional measures. A cohort of osteoarthritis patients was imaged using a 1.0 T MR scanner over a 36-month period. Hyaline cartilage was manually segmented from a three-dimensional (3D) spoiled gradient-echo sequence with fat suppression. Representative outlines of the bone surfaces of the distal femur and proximal tibia were automatically generated from T₂ weighted images using statistical models of the shape and appearance of the bones. Cartilage thickness was measured from a dense set of points representing the bony surface. The models of the bones provided a common frame of reference, relative to which change maps were generated and aggregated across the cohort and anatomically corresponding subregions of the joint to be identified. In the reproducibility arm involving six patients, the thickness of cartilage had coefficients of variation of 2.66% within the tibiofemoral joint and 2.94% within the medial femoral condyle region. In the 9 patients (6 female, 3 male) who completed the 36-month study, the most striking observation was that lack of change in global measures of cartilage thickness concealed substantial focal changes. Specifically, the cartilage thickness within the tibiofemoral joint decreased by 0.85% per annum (95% CI -2.13% to 0.45%) with the medial femoral condyle as the region with the most significant change, decreasing by 2.43% per annum (uncorrected 95% CI -4.31% to 0.51%).

Evaluation of segmentation methods on head and neck CT: Auto‐segmentation challenge 2015

Purpose Automated delineation of structures and organs is a key step in medical imaging. However, due to the large number and diversity of structures and the large variety of segmentation algorithms, a consensus is lacking as to which automated segmentation method works best for certain applications. Segmentation challenges are a good approach for unbiased evaluation and comparison of segmentation algorithms. Methods In this work, we describe and present the results of the Head and Neck Auto‐Segmentation Challenge 2015, a satellite event at the Medical Image Computing and Computer Assisted Interventions (MICCAI) 2015 conference. Six teams participated in a challenge to segment nine structures in the head and neck region of CT images: brainstem, mandible, chiasm, bilateral optic nerves, bilateral parotid glands, and bilateral submandibular glands. Results This paper presents the quantitative results of this challenge using multiple established error metrics and a well‐defined ranking system. The strengths and weaknesses of the different auto‐segmentation approaches are analyzed and discussed. Conclusions The Head and Neck Auto‐Segmentation Challenge 2015 was a good opportunity to assess the current state‐of‐the‐art in segmentation of organs at risk for radiotherapy treatment. Participating teams had the possibility to compare their approaches to other methods under unbiased and standardized circumstances. The results demonstrate a clear tendency toward more general purpose and fewer structure‐specific segmentation algorithms.

The relationship between clinical characteristics, radiographic osteoarthritis and 3D bone area: data from the Osteoarthritis Initiative

Summary Background Radiographic measures of osteoarthritis (OA) are based upon two dimensional projection images. Active appearance modelling (AAM) of knee magnetic resonance imaging (MRI) enables accurate, 3D quantification of joint structures in large cohorts. This cross-sectional study explored the relationship between clinical characteristics, radiographic measures of OA and 3D bone area (tAB). Methods Clinical data and baseline paired radiographic and MRI data, from the medial compartment of one knee of 2588 participants were obtained from the NIH Osteoarthritis Initiative (OAI). The medial femur (MF) and tibia (MT) tAB were calculated using AAM. ‘OA-attributable’ tAB (OA-tAB) was calculated using data from regression models of tAB of knees without OA. Associations between OA-tAB and radiographic measures of OA were investigated using linear regression. Results In univariable analyses, height, weight, and age in female knees without OA explained 43.1%, 32.1% and 0.1% of the MF tAB variance individually and 54.4% when included simultaneously in a multivariable model. Joint space width (JSW), osteophytes and sclerosis explained just 5.3%, 14.9% and 10.1% of the variance of MF OA-tAB individually and 17.4% when combined. Kellgren Lawrence (KL) grade explained approximately 20% of MF OA-tAB individually. Similar results were seen for MT OA-tAB. Conclusion Height explained the majority of variance in tAB, confirming an allometric relationship between body and joint size. Radiographic measures of OA, derived from a single radiographic projection, accounted for only a small amount of variation in 3D knee OA-tAB. The additional structural information provided by 3D bone area may explain the lack of a substantive relationship with these radiographic OA measures.

The relationship between three-dimensional knee MRI bone shape and total knee replacement—a case control study: data from the Osteoarthritis Initiative

Objective. There is growing understanding of the importance of bone in OA. Our aim was to determine the relationship between 3D MRI bone shape and total knee replacement (TKR). Methods. A nested case-control study within the Osteoarthritis Initiative cohort identified case knees with confirmed TKR for OA and controls that were matched using propensity scores. Active appearance modelling quantification of the bone shape of all knee bones identified vectors between knees having or not having OA. Vectors were scaled such that −1 and +1 represented the mean non-OA and mean OA shapes. Results. Compared to controls (n = 310), TKR cases (n = 310) had a more positive mean baseline 3D bone shape vector, indicating more advanced structural OA, for the femur [mean 0.98 vs −0.11; difference (95% CI) 1.10 (0.88, 1.31)], tibia [mean 0.86 vs −0.07; difference (95% CI) 0.94 (0.72, 1.16)] and patella [mean 0.95 vs 0.03; difference (95% CI) 0.92 (0.65, 1.20)]. Odds ratios (95% CI) for TKR per normalized unit of 3D bone shape vector for the femur, tibia and patella were: 1.85 (1.59, 2.16), 1.64 (1.42, 1.89) and 1.36 (1.22, 1.50), respectively, all P < 0.001. After including Kellgren–Lawrence grade in a multivariable analysis, only the femur 3D shape vector remained significantly associated with TKR [odds ratio 1.24 (1.02, 1.51)]. Conclusion. 3D bone shape was associated with the endpoint of this study, TKR, with femoral shape being most associated. This study contributes to the validation of quantitative MRI bone biomarkers for OA structure-modification trials.