Novel Biomarkers For Predicting Knee OA Progression

Researchers have found several biomarkers that hold promise as predictors of pain and structural worsening of knee osteoarthritis

Researchers have found several biomarkers that hold promise as predictors of pain and structural worsening of knee osteoarthritis (OA).

“A cure for osteoarthritis remains elusive and [its] management is largely palliative. The progression of knee OA is highly variable and difficult to predict [with] currently available clinical and imaging measures,” wrote Virginia Byers Kraus, MD, PhD, of the Duke Molecular Physiology Institute and Division of Rheumatology at Duke University School of Medicine in Durham, North Carolina and her colleagues.  “At present, there are no disease-modifying OA drugs approved by the US Food and Drug Administration (FDA) or European Medicines Agency.”

Some of the main obstacles to efficiently developing structure-modifying therapies for OA include its low responsiveness to change, and, at most, only a moderate correlation between radiographic data and clinical endpoints.

“The ultimate goals of this work are to provide new drug development tools to effectively enrich OA clinical trials with faster progressors and to qualify biomarker candidates that might serve as surrogates of efficacy in OA trials,” wrote Dr Byers Kraus and colleagues.

For this study, researchers investigated a targeted set of 18 biochemical biomarkers in serum and/or urine for their ability to predict knee OA-related radiographic and persistent pain progression over a 24 to 48 month follow-up compared with baseline.

High Yield Data Summary

  • The 12- and 24-month time-integrated concentrations of 8 catabolic biomarkers hold promise as predictors of pain and radiographic structural worsening of OA over 48 months. These included uCTXII, uC2C-HUSA, sHA, sNTXI, uNTXI,uCTXIα, uCTXIβ, sCTXI, and one anabolic biomarker, sPIIANP

They investigated 194 knees with OA as well as radiographic and persistent pain that worsened from 24 to 48 months in participants from the osteoarthritis initiative (OAI). They also investigated 406 control knees that lacked the combination of radiographic and pain progression needed for the experimental group. 

Comparator knees consisted of 3 subgroups: those with radiographic progression but not pain progression in either the study or contralateral knee (n=103); pain progression but not radiographic progression in either knee (n=103); and OA non-progressors (n=200) with no radiographic and no pain progression in either knee.

The 18 biomarkers were agreed upon through consensus of the Osteoarthritis Research Society International (OARSI)/FDA Biomarkers Working Group, and were measured at baseline, 12 months, and 24 months.

Biomarkers analyzed in serum alone were cartilage oligomeric matrix protein (COMP), hyaluronan (HA), C-propeptide of type II collagen, N-terminal propeptide of collagen IIA (PIIANP), chondroitin sulfate 846 epitope, the C-terminal crosslinked telopeptide of type I collagen (CTXI) and matrix metalloproteinase 3. 

Biomarkers analyzed in serum and urine were Col2-3/4 C-terminal cleavage product of types I and II collagen (C1, 2C), Col2-3/4 C-terminal cleavage product of type II collagen human urine sandwich assay (C2C-Human Urine Sandwich Assay (HUSA) in serum, C2C-HUSA HUSA in urine), nitrated epitope of the α-helical region of type II collagen (Coll2-1 NO2) and the crosslinked N-telopeptide of type I collagen (NTXI). 

Biomarkers analyzed in urine alone were the C-terminal crosslinked telopeptide type II collagen (CTXII), and alpha and beta isomerised versions of the CTXI (CTXIα and CTXIβ).

The researchers found that the 24- month time-integrated concentrations of 8 biomarkers significantly predicted case status (ORs per 1 SD change in biomarker): sCTXI 1.28, sHA 1.22, sNTXI 1.25, uC2CHUSA 1.27, uCTXII 1.37, uNTXI 1.29, uCTXIα 1.32, uCTXIβ 1.27.

At 24 months, the time-integrated concentrations of uCTXII (1.47–1.72) and uC2C-Human Urine Sandwich Assay (HUSA) (1.36–1.50) both predicted individual group status (pain worsening, joint space loss and their combination). The most predictive and parsimonious combinatorial model for case status consisted of 24 M TIC uCTXII, sHA and sNTXI (AUC 0.667 adjusted). Baseline uCTXII and uCTXIα both significantly predicted case status (OR 1.29 and 1.20, respectively).

Summary & Clinical Applicability

The researchers concluded that this study is important for establishing a paradigm for proceeding with OA-related biomarker qualification.

They found that the 12- and 24-month time-integrated concentrations of 8 catabolic biomarkers hold promise as predictors of pain and radiographic structural worsening of OA over 48 months, including: uCTXII, uC2C-HUSA, sHA, sNTXI, uNTXI,uCTXIα, uCTXIβ, sCTXI (OR 1.22–1.72 depending upon comparator group), and one anabolic biomarker, sPIIANP (OR 0.79–0.83 depending upon comparator group).

“Although only modestly predictive of single knee progression, given their cost effectiveness, they might have some utility for enriching OA trials for progressors or providing early proof of effectiveness of a drug to prevent OA progression,” the researchers wrote. 

Limitations & Disclosures

-The study only took into account the knee status and did not take into account OA status at other joint sites.

-While the researchers selected all possible cases from OAI, there was a limitation of sample size; instead of formal adjustment for multiple comparisons, they used a number of complementary statistical approaches to evaluate discriminatory power of each biomarker, including c-statistics, NRI, and 10-fold cross-validation.

-The researchers noted that other approaches to data reduction, selection of variables for multivariate analysis, and multivariate modeling, may give results different from what was found in the study, for the most predictive and parsimonious multivariable models.

“These results will require additional verification, ideally in extant clinical trials, to be formally qualified by the FDA as Drug Development Tools as described in FDA guidance. Additional biomarkers in development will no doubt add to what appears to be a very promising future,” the authors cautioned.


Byers Kraus V, Collins JE, Hargrove D, et al. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers ConsortiumAnn Rheum Dis. 2016; doi:10.1136/annrheumdis-2016-209252.

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