C. Ladel

Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future.

Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes.

Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria

OBJECTIVE To review and summarize biomarker data published from April 2014 to May 2015 to provide insight to the ongoing work in the field of osteoarthritis (OA). Furthermore, to summarize the BIPED criteria and set it in context of the medical needs of 2015. METHODS PubMed was used as searching machine: Time period 2014/04/01-2015/05/01, MeSH term [Biomarker] AND [Osteoarthritis], Language; English, Full text available. Reviews were excluded. Only papers describing protein based biomarkers measured in human body fluids from OA patients were included. RESULTS Biomarkers of joint tissue turnover, cytokines, chemokines and peptide arrays were measured in different cohorts and studies. Amongst those were previously tested biomarkers such as osteocalcin, Carboxy-terminal cross-linked fragment of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP). A majority of the biomarker were classified as I, B or B biomarkers according to the BIPED criteria. Work is continuing on testing biomarkers in OA. There is still a huge, unmet medical need to identify, test, validate and qualify novel and well-known biomarkers. A pre-requisite for this is better characterization and classification of biomarkers to their needs, which may not be reached before higher understanding of OA phenotypes has been gained. In addition, we provide some references to some recent guidelines from Food and Drug Administration (FDA) and European Medicines Agency (EMA) on qualification and usage of biomarkers for drug development and personalized medicine, which may provide value to the field.

Trajectory of cartilage loss within 4 years of knee replacement - a nested case-control study from the Osteoarthritis Initiative

OBJECTIVE Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior to KR vs non-replaced controls. METHODS A nested case-control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence (T0), and at 1-4 years prior to T0 (T-1 to T-4). Cartilage loss between cases and controls was compared using paired t-tests and conditional logistic regression. RESULTS One hundred and eighty-nine knees of 164 OAI participants [55% women; age 64 ± 8.7; body mass index (BMI) 29 ± 4.5] had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls [94 ± 137 vs 55 ± 104 μm; P = 0.0017 (paired t); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08-1.70)]. The discrimination was stronger for T-2 → T0 [OR 1.61 (1.33-1.95), n = 127] than for T-1 → T0, and was not statistically significant for intervals prior to T-2 [i.e., T-4 → T-2, OR 0.97 (0.67-1.41), n = 60]. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI. CONCLUSIONS In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined.

Synovitis biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory osteoarthritis

Abstract Objective: Characterize biomarkers measuring extracellular matrix turnover of inflamed osteoarthritis synovium. Methods: Human primary fibroblast-like synoviocytes and synovial membrane explants (SMEs) treated with various cytokines and growth factors were assessed by C1M, C3M, and acMMP3 in the conditioned medium. Results: TNFα significantly increased C1M up to seven-fold (p = 0.0002), C3M up to 24-fold (p = 0.0011), and acMMP3 up to 14-fold (p < 0.0001) in SMEs. IL-1β also significantly increased C1M up to five-fold (p = 0.00094), C3M four-fold (p = 0.007), and acMMP3 18-fold (p < 0.0001) in SMEs. Conclusion: The biomarkers C1M, C3M, and acMMP-3 were synovitis biomarkers ex vivo and provide a translational tool together with the SME model.

Rates and sensitivity of knee cartilage thickness loss in specific central reading radiographic strata from the osteoarthritis initiative.

OBJECTIVE To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. METHODS One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). RESULTS The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 μm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 ± 159 vs -31 ± 126 μm; P = 0.02). For comparison, the loss in grade3 knees was -72 ± 122 μm. CONCLUSIONS In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs).

The association between biochemical markers of bone turnover and bone changes on imaging – Data from the Osteoarthritis Initiative

To determine the relationship between biochemical markers involved in bone turnover and bone features on imaging in knees with osteoarthritis (OA).

Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants With Incident Total Knee Arthroplasty: A Prospective Cohort Study

To explore whether baseline to 12‐month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non‐TKA).

Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants with Incident Knee Replacement: a Prospective Cohort Study

To explore whether baseline to 12‐month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non‐TKA).

Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants With Incident Total Knee Arthroplasty: A Prospective Cohort Study: Cartilage Loss and Incident Knee Replacment

To explore whether baseline to 12‐month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non‐TKA).