International Journal of Molecular Sciences · 9 authors, 5 centres
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This study found that nitisinone treatment in alkaptonuria patients alters biomarkers of bone and cartilage remodelling, with an initial increase in bone turnover markers and a sustained decrease in cartilage degradation markers. The reduction in cartilage remodelling biomarkers was more pronounced in younger and male patients, suggesting early treatment may be beneficial. These biomarkers could help monitor disease progression and guide therapy in alkaptonuria.
**Background:** Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by deficiency of homogentisate 1,2-dioxygenase, leading to accumulation of homogentisic acid and ochronotic pigment deposition in connective tissues, particularly cartilage. This causes severe spondyloarthropathy, osteopenia, and other manifestations. Nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, reduces homogentisic acid by 99.7% and slows disease progression. Non-invasive biomarkers of extracellular matrix remodelling could help monitor disease and treatment effects. This study evaluated biomarkers of type I and II collagen turnover in the SONIA 2 trial.
**Methods:** SONIA 2 was a 4-year, open-label, evaluator-blind, multicentre, randomized, no-treatment controlled, parallel-group study. 138 patients with AKU were enrolled; 69 received 10 mg nitisinone daily (10 patients reduced to 2 mg due to corneal keratopathy) and 69 received no treatment. Serum and urine samples were collected at baseline and yearly for 4 years. Biomarkers measured included serum CTX-I (bone resorption), serum PRO-C1 (bone formation), urine CTX-II/Creat (cartilage remodelling), and serum C2M (cartilage remodelling). Alkaline phosphatase (ALP) was also measured. Statistical analyses used longitudinal linear models with generalized least squares, adjusting for treatment, site, age category, visit, and baseline biomarker levels.
**Key Results:** At baseline, no significant demographic differences existed between groups. Median age was 50 years, 60% male, median BMI 26 kg/m². At end of study, CTX-II/Creat increased significantly in controls (from 660.0 to 971.9 ng/mmol, p<0.01) but not in nitisinone-treated patients (713.9 to 727.4 ng/mmol). Trajectory analysis showed that after one year, bone remodelling biomarkers increased significantly in nitisinone-treated patients: CTX-I by 19% (95% CI 5%-36%) and PRO-C1 by 40% (95% CI 19%-65%), returning to control levels later. Cartilage remodelling biomarkers decreased: CTX-II/Creat was suppressed by 27% (95% CI 11%-40%) at Year 3 and 26% (95% CI 8%-41%) at Year 4; C2M was suppressed by 9.4% (95% CI 3%-15%) at Year 1. Stratification showed CTX-II/Creat reduction was significant only in younger patients (≤55 years) and males; C2M reduction was significant only in males and patients with lower baseline cAKUSSI (below median). Baseline CTX-II/Creat correlated moderately with osteoarticular disease parameters (Spearman r=0.29-0.51, p=0.02 to p<0.0001) and negatively with bone density T-score (r=-0.5, p<0.0001). CTX-I was higher in males. No significant interaction with antiresorptive treatment was found.
**Clinical Implications:** Nitisinone treatment alters bone and cartilage remodelling in AKU, with an initial increase in bone turnover followed by normalization, and a sustained reduction in cartilage degradation. The greater effect on cartilage biomarkers in younger and less severely affected patients suggests early treatment initiation may be beneficial. These non-invasive biomarkers could help identify patients with early joint involvement and monitor long-term treatment effects, potentially reducing the need for complex clinical and imaging evaluations. The study is limited by the relatively small sample size (though large for a rare disease) and the 4-year follow-up, which may be insufficient to see full remodelling changes.