Perspective | Published:


The role of radiography and MRI for eligibility assessment in DMOAD trials of knee OA


Currently, no disease-modifying osteoarthritis drugs (DMOADs) have been approved. Past clinical trials have failed for several reasons, including the commonly applied definition of eligibility based on radiographic assessment of joint structure. In the context of precision medicine, finding the appropriate patient for a specific treatment approach will be of increasing relevance. Phenotypic stratification by use of imaging at the time of determining eligibility for clinical trials will be paramount and cannot be achieved using radiography alone. Furthermore, identification of joints at high risk of rapid progression of osteoarthritis is needed in order to enable a more efficient DMOAD trial design. In addition, joints at high risk of collapse need to be excluded at screening. The use of MRI might offer advantages over radiography in this context. Technological advances and simplified image assessment address many of the commonly perceived barriers to the application of MRI to assessment of eligibility for DMOAD clinical trials.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Karsdal, M. A. et al. The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study. Osteoarthritis Cartilage 18, 150–159 (2010).

  2. 2.

    Spector, T. D. et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res. Ther. 7, R625–R633 (2005).

  3. 3.

    Alexandersen, P., Karsdal, M. A., Byrjalsen, I. & Christiansen, C. Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis. Climacteric 14, 236–243 (2011).

  4. 4.

    Reginster, J. Y. et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann. Rheum. Dis. 72, 179–186 (2013).

  5. 5.

    DiMasi, J. A., Grabowski, H. G. & Hansen, R. W. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33 (2016).

  6. 6.

    Kellgren, J. H. & Lawrence, J. S. Radiological assessment of osteo-arthrosis. Ann. Rheum. Dis. 16, 494–502 (1957).

  7. 7.

    Hellio Le Graverand, M. P. et al. Considerations when designing a disease-modifying osteoarthritis drug (DMOAD) trial using radiography. Semin. Arthritis Rheum. 43, 1–8 (2013).

  8. 8.

    Guermazi, A. et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). BMJ 345, e5339 (2012).

  9. 9.

    Yusuf, E., Kortekaas, M. C., Watt, I., Huizinga, T. W. & Kloppenburg, M. Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. Ann. Rheum. Dis. 70, 60–67 (2011).

  10. 10.

    Hayashi, D. et al. Pre-radiographic osteoarthritic changes are highly prevalent in the medial patella and medial posterior femur in older persons: Framingham OA study. Osteoarthritis Cartilage 22, 76–83 (2014).

  11. 11.

    Hayashi, D., Jarraya, M., A., G. & Roemer, F. Frequency and fluctuation of susceptibility artifacts in the tibiofemoral joint space in painful knees on 3T MRI and association with meniscal tears, radiographic joint space narrowing and calcifications. Arthritis Rheum. 64, 1030 (2012).

  12. 12.

    Nelson, A. E. et al. Differences in multijoint radiographic osteoarthritis phenotypes among African Americans and Caucasians: the Johnston County Osteoarthritis project. Arthritis Rheum. 63, 3843–3852 (2011).

  13. 13.

    Bijlsma, J. W., Berenbaum, F. & Lafeber, F. P. Osteoarthritis: an update with relevance for clinical practice. Lancet 377, 2115–2126 (2011).

  14. 14.

    Deveza, L. A. et al. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage 25, 1926–1941 (2017).

  15. 15.

    Kinds, M. B. et al. Influence of variation in semiflexed knee positioning during image acquisition on separate quantitative radiographic parameters of osteoarthritis, measured by Knee Images Digital Analysis. Osteoarthritis Cartilage 20, 997–1003 (2012).

  16. 16.

    Lawrence, J. S., Bremner, J. M. & Bier, F. Osteo-arthrosis. Prevalence in the population and relationship between symptoms and x-ray changes. Ann. Rheum. Dis. 25, 1–24 (1966).

  17. 17.

    Hannan, M. T., Felson, D. T. & Pincus, T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J. Rheumatol. 27, 1513–1517 (2000).

  18. 18.

    Neogi, T. et al. Association of joint inflammation with pain sensitization in knee osteoarthritis: the Multicenter Osteoarthritis Study. Arthritis Rheumatol. 68, 654–661 (2016).

  19. 19.

    Neogi, T. et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ 339, b2844 (2009).

  20. 20.

    Baker, K. et al. Relation of synovitis to knee pain using contrast-enhanced MRIs. Ann. Rheum. Dis. 69, 1779–1783 (2012).

  21. 21.

    Kornaat, P. R. et al. Osteoarthritis of the knee: association between clinical features and MR imaging findings. Radiology 239, 811–817 (2006).

  22. 22.

    Neogi, T. Structural correlates of pain in osteoarthritis. Clin. Exp. Rheumatol. 35 (Suppl. 107), 75–78 (2017).

  23. 23.

    Zhang, Y. et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum. 63, 691–699 (2011).

  24. 24.

    Brandt, K. D. & Mazzuca, S. A. Lessons learned from nine clinical trials of disease-modifying osteoarthritis drugs. Arthritis Rheum. 52, 3349–3359 (2005).

  25. 25.

    Karsdal, M. A. et al. Osteoarthritis — a case for personalized health care? Osteoarthritis Cartilage 22, 7–16 (2014).

  26. 26.

    Karsdal, M. A. et al. OA phenotypes, rather than disease stage, drive structural progression — identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA. Osteoarthritis Cartilage 23, 550–558 (2015).

  27. 27.

    Roemer, F. W. et al. Prevalence of magnetic resonance imaging-defined atrophic and hypertrophic phenotypes of knee osteoarthritis in a population-based cohort. Arthritis Rheum. 64, 429–437 (2012).

  28. 28.

    Yamamoto, T. & Bullough, P. G. Spontaneous osteonecrosis of the knee: the result of subchondral insufficiency fracture. J. Bone Joint Surg. Am. 82, 858–866 (2000).

  29. 29.

    Lecouvet, F. E. et al. Early irreversible osteonecrosis versus transient lesions of the femoral condyles: prognostic value of subchondral bone and marrow changes on MR imaging. AJR Am. J. Roentgenol. 170, 71–77 (1998).

  30. 30.

    Plett, S. K. et al. Femoral condyle insufficiency fractures: associated clinical and morphological findings and impact on outcome. Skeletal Radiol. 44, 1785–1794 (2015).

  31. 31.

    Hayashi, D., Guermazi, A. & Roemer, F. W. MRI of osteoarthritis: the challenges of definition and quantification. Semin. Musculoskelet. Radiol. 16, 419–430 (2012).

  32. 32.

    Roemer, F. W., Crema, M. D., Trattnig, S. & Guermazi, A. Advances in imaging of osteoarthritis and cartilage. Radiology 260, 332–354 (2011).

  33. 33.

    Fritz, J. et al. Three-dimensional CAIPIRINHA SPACE TSE for 5-minute high-resolution MRI of the knee. Invest. Radiol. 51, 609–617 (2016).

  34. 34.

    Fritz, J. et al. Simultaneous multislice accelerated turbo spin echo magnetic resonance imaging: comparison and combination with in-plane parallel imaging acceleration for high-resolution magnetic resonance imaging of the knee. Invest. Radiol. 52, 529–537 (2017).

  35. 35.

    Altahawi, F. F., Blount, K. J., Morley, N. P., Raithel, E. & Omar, I. M. Comparing an accelerated 3D fast spin-echo sequence (CS-SPACE) for knee 3-T magnetic resonance imaging with traditional 3D fast spin-echo (SPACE) and routine 2D sequences. Skeletal Radiol. 46, 7–15 (2017).

  36. 36.

    Schnaiter, J. W. et al. Diagnostic accuracy of an MRI protocol of the knee accelerated through parallel imaging in correlation to arthroscopy. Rofo 190, 265–272 (2018).

  37. 37.

    Peterfy, C. G. et al. Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage 12, 177–190 (2004).

  38. 38.

    Kornaat, P. R. et al. MRI assessment of knee osteoarthritis: Knee Osteoarthritis Scoring System (KOSS) — inter-observer and intra-observer reproducibility of a compartment-based scoring system. Skeletal Radiol. 34, 95–102 (2005).

  39. 39.

    Hunter, D. J. et al. The reliability of a new scoring system for knee osteoarthritis MRI and the validity of bone marrow lesion assessment: BLOKS (Boston Leeds Osteoarthritis Knee Score). Ann. Rheum. Dis. 67, 206–211 (2008).

  40. 40.

    Roemer, F. W. et al. The association between meniscal damage of the posterior horns and localized posterior synovitis detected on T1-weighted contrast-enhanced MRI — the MOST study. Semin. Arthritis Rheum. 42, 573–581 (2013).

  41. 41.

    Guermazi, A. et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann. Rheum. Dis. 70, 805–811 (2011).

  42. 42.

    Niu, J. et al. Patterns of coexisting lesions detected on magnetic resonance imaging and relationship to incident knee osteoarthritis: the Multicenter Osteoarthritis Study. Arthritis Rheumatol. 67, 3158–3165 (2015).

  43. 43.

    Waarsing, J. H., Bierma-Zeinstra, S. M. & Weinans, H. Distinct subtypes of knee osteoarthritis: data from the Osteoarthritis Initiative. Rheumatology 54, 1650–1658 (2015).

  44. 44.

    Pelletier, J. P., Martel-Pelletier, J. & Abramson, S. B. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 44, 1237–1247 (2001).

  45. 45.

    Ayral, X., Pickering, E., Woodworth, T., Mackillop, N. & Dougados, M. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis — results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage 13, 361–367 (2005).

  46. 46.

    Roemer, F. W. et al. MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis. Osteoarthritis Cartilage 17, 1115–1131 (2009).

  47. 47.

    Felson, D. T. et al. The association of bone marrow lesions with pain in knee osteoarthritis. Ann. Intern. Med. 134, 541–549 (2001).

  48. 48.

    Roemer, F. W. et al. Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST study. A longitudinal multicenter study of knee osteoarthritis. Ann. Rheum. Dis. 68, 1461–1465 (2008).

  49. 49.

    Felson, D. T. et al. Bone marrow edema and its relation to progression of knee osteoarthritis. Ann. Intern. Med. 139, 330–336 (2003).

  50. 50.

    Englund, M., Roemer, F. W., Hayashi, D., Crema, M. D. & Guermazi, A. Meniscus pathology, osteoarthritis and the treatment controversy. Nat. Rev. Rheumatol. 8, 412–419 (2012).

  51. 51.

    Jarraya, M. et al. Meniscus morphology: does tear type matter? A narrative review with focus on relevance for osteoarthritis research. Semin. Arthritis Rheum. 46, 552–561 (2017).

  52. 52.

    Hunter, D. J. et al. The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis. Arthritis Rheum. 54, 795–801 (2006).

  53. 53.

    Sharma, L. et al. Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees. Arthritis Rheum. 58, 1716–1726 (2008).

  54. 54.

    Crema, M. D. et al. Factors associated with meniscal extrusion in knees with or at risk for osteoarthritis: the Multicenter Osteoarthritis study. Radiology 264, 494–503 (2012).

  55. 55.

    Crema, M. D. et al. Is the atrophic phenotype of tibiofemoral osteoarthritis associated with faster progression of disease? The MOST study. Osteoarthritis Cartilage 25, 1647–1653 (2017).

  56. 56.

    Roemer, F. W. et al. Risk factors for magnetic resonance imaging-detected patellofemoral and tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study. Arthritis Rheum. 64, 1888–1898 (2012).

  57. 57.

    Roemer, F. W. et al. Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study. Radiology 252, 772–780 (2009).

  58. 58.

    Wilmot, A. S., Ruutiainen, A. T., Bakhru, P. T., Schweitzer, M. E. & Shabshin, N. Subchondral insufficiency fracture of the knee: a recognizable associated soft tissue edema pattern and a similar distribution among men and women. Eur. J. Radiol. 85, 2096–2103 (2016).

  59. 59.

    Allaire, R., Muriuki, M., Gilbertson, L. & Harner, C. D. Biomechanical consequences of a tear of the posterior root of the medial meniscus. Similar to total meniscectomy. J. Bone Joint Surg. Am. 90, 1922–1931 (2008).

  60. 60.

    Hein, C. N., Deperio, J. G., Ehrensberger, M. T. & Marzo, J. M. Effects of medial meniscal posterior horn avulsion and repair on meniscal displacement. Knee 18, 189–192 (2011).

  61. 61.

    LaPrade, C. M. et al. Altered tibiofemoral contact mechanics due to lateral meniscus posterior horn root avulsions and radial tears can be restored with in situ pull-out suture repairs. J. Bone Joint Surg. Am. 96, 471–479 (2014).

  62. 62.

    Marzo, J. M. & Gurske-DePerio, J. Effects of medial meniscus posterior horn avulsion and repair on tibiofemoral contact area and peak contact pressure with clinical implications. Am. J. Sports Med. 37, 124–129 (2009).

  63. 63.

    Schillhammer, C. K., Werner, F. W., Scuderi, M. G. & Cannizzaro, J. P. Repair of lateral meniscus posterior horn detachment lesions: a biomechanical evaluation. Am. J. Sports Med. 40, 2604–2609 (2012).

  64. 64.

    LaPrade, C. M. et al. Biomechanical consequences of a nonanatomic posterior medial meniscal root repair. Am. J. Sports Med. 43, 912–920 (2015).

  65. 65.

    Ra, H. J., Ha, J. K., Jang, H. S. & Kim, J. G. Traumatic posterior root tear of the medial meniscus in patients with severe medial instability of the knee. Knee Surg. Sports Traumatol. Arthrosc. 23, 3121–3126 (2015).

  66. 66.

    Henry, S. et al. Medial meniscus tear morphology and chondral degeneration of the knee: is there a relationship? Arthroscopy 28, 1124–1134.e2 (2012).

  67. 67.

    James, S. L., Panicek, D. M. & Davies, A. M. Bone marrow oedema associated with benign and malignant bone tumours. Eur. J. Radiol. 67, 11–21 (2008).

  68. 68.

    Ehara, S. et al. Peritumoral edema in osteoid osteoma on magnetic resonance imaging. Skeletal Radiol. 28, 265–270 (1999).

  69. 69.

    Podlipska, J. et al. Comparison of diagnostic performance of semi-quantitative knee ultrasound and knee radiography with MRI: Oulu Knee Osteoarthritis Study. Sci. Rep. 6, 22365 (2016).

  70. 70.

    Bruyn, G. A. et al. An OMERACT reliability exercise of inflammatory and structural abnormalities in patients with knee osteoarthritis using ultrasound assessment. Ann. Rheum. Dis. 75, 842–846 (2016).

  71. 71.

    Hall, M. et al. Synovial pathology detected on ultrasound correlates with the severity of radiographic knee osteoarthritis more than with symptoms. Osteoarthritis Cartilage 22, 1627–1633 (2014).

  72. 72.

    Parsons, M. A. et al. Increased 18F-FDG uptake suggests synovial inflammatory reaction with osteoarthritis: preliminary in-vivo results in humans. Nucl. Med. Commun. 36, 1215–1219 (2015).

  73. 73.

    Mazzuca, S. A. et al. Severity of joint pain and Kellgren–Lawrence grade at baseline are better predictors of joint space narrowing than bone scintigraphy in obese women with knee osteoarthritis. J. Rheumatol. 32, 1540–1546 (2005).

  74. 74.

    Guermazi, A., Hayashi, D., Roemer, F. W. & Felson, D. T. Osteoarthritis: a review of strengths and weaknesses of different imaging options. Rheum. Dis. Clin. North Am. 39, 567–591 (2013).

  75. 75.

    Omoumi, P., Mercier, G. A., Lecouvet, F., Simoni, P. & Vande Berg, B. C. CT arthrography, MR arthrography, PET, and scintigraphy in osteoarthritis. Radiol. Clin. North Am. 47, 595–615 (2009).

Download references

Author information

F.W.R. researched data for the article. F.W.R. and A.G. wrote the article. All authors made a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

Competing interests

F.W.R. declares that he holds shares in Boston Imaging Core Lab, LLC. C.K.K. declares that he has received research grants from Abbvie and EMD Serono and has acted as a consultant for Astellas, EMD Serono, Fidia and Thusane. A.G. declares that he holds shares in and is president of Boston Imaging Core Lab, LLC and that he has acted as a consultant for Astra Zeneca, General Electric, Merck Serono, OrthoTrophix, Pfizer, Tissue Gene, and Sanofi. D.H. and D.T.F. declare no competing interests.

Correspondence to Frank W. Roemer.

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Further reading

Fig. 1: Radiographically normal knees are frequently not structurally normal on MRI.
Fig. 2: Influence of knee positioning on radiographic imaging of joint space width.
Fig. 3: Identifying the underlying pathology leading to knee pain in osteoarthritis by MRI.
Fig. 4: Structural phenotypes of osteoarthritis as defined by MRI.
Fig. 5: Joint space narrowing on radiographs could be a result of cartilage damage, meniscal damage or meniscal extrusion or a combination of these features.
Fig. 6: Exclusionary findings in screening for eligibility for clinical trials of potential DMOADs.