The levels of urine C-telopeptide of cross-linked collagen type II (uCTX-II) were found to be independently associated with pain intensity and radiographic severity in patients with osteoarthritis (OA), according to study results published in Arthritis Research & Therapy.

Urine levels of a type II collagen degradation product (uCTX-II) have been associated with disease severity in OA. However, the tissue origin of this biomarker is uncertain. Investigators sought to determine the pathologic relevance in OA of uCTX-II, serum osteocalcin, and uCTX-I.

In this cross-sectional post hoc analysis, the baseline data from 2 different multicenter randomized double-blinded placebo-controlled phase 3 trials ( identifiers: NCT00486434 and NCT00704847) were examined. These trials aimed to assess the efficacy of salmon calcitonin on painful knee OA in patients aged 51 to 80 years. Only participants with available urine specimens and bilateral knee radiographs (n=1241; mean age, 64.6 years; 67.8% women) were considered.

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The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to evaluate pain intensity, and Kellgren-Lawrence (KL) grading was used to assess radiographic severity. Bilateral knee pain, gender, and KL scores were examined for associations with uCTX-I, osteocalcin, and uCTX-II levels to evaluate joint contributions at different OA stages.

Associations were established between uCTX-II levels and age (P =.01-.02), female gender (P <.001), body mass index (BMI; P =.02-.03), WOMAC pain (P =.03) and KL grade (P <.001) after multivariable adjustments. Weight-bearing pain, but not non-weight-bearing pain, was found to be associated with uCTX-II. The levels of uCTX-II were found to increase with the radiographic severity of single knee joints.

uCTX-I and osteocalcin levels were found to be associated with gender and BMI, but no correlation was established between these biomarkers and radiographic severity. When men and women with identical KL scores were compared, women were found to have higher biomarker levels in several, but not all, KL groups. Modest but significant correlations were found between levels of uCTX-II and levels of uCTX-I and osteocalcin (r = 0.337 and 0.210, respectively; P <.0001 for both).

Study limitations include the lack of radiographic evaluations of structures other than knees, potential other confounders, and a cross-sectional design that precluded causal inference.

“Our data support prior results indicating that uCTX-II is an important biomarker in OA. The data suggest that biomarker differences between genders should be taken into account when evaluating these markers in the context of structural features of OA,” noted the study authors. They recommended that future research involve longitudinal trials that examine the gender relevance of these biomarkers.

Disclosures: The trials were co-funded by Nordic Bioscience and Novartis AG.

ARB, IB, ACBJ, CC, BJR, JRA and MAK are full-time employees of Nordic Bioscience, a company engaged in biomarker research and development of treatments for osteoarthritis. The ELISA assays for uCTX-I, uCTX-II and N-MID osteocalcin were developed by Nordic Bioscience but were acquired by Immunodiagnostic Systems UK as Urine Beta Crosslaps®, Urine Cartilaps® and NMID® Osteocalcin respectively in 2007. ARB, ACBJ, CC, BJR, JRA and MK are shareholders of Nordic Bioscience. BJR and CC are major shareholders and board members of Nordic Bioscience.


Bihlet AR, Byrjalsen I, Bay-Jensen A-C, et al. Associations between biomarkers of bone and cartilage turnover, gender, pain categories and radiographic severity in knee osteoarthritis. Arthritis Res Ther. 2019;21(1):1-10. doi:10.1186/s13075-019-1987-7

This article originally appeared on Clinical Pain Advisor