Prednisone, not vamorolone, suppresses novel serum bone and cartilage biomarkers associated with growth failure in children with Duchenne muscular dystrophy.

Corticosteroids are among the most highly prescribed drugs. Chronic treatment with corticosteroids causes osteopenia, as well as growth failure in children. Our goal was to identify serum biomarkers of prednisone-related perturbations of bone and/or cartilage metabolism associated with growth failure in children. We utilized longitudinal serum samples from a double-blind, placebo- and prednisone-controlled trial of vamorolone in 4 to < 7 years children with Duchenne muscular dystrophy assayed by proteomic methods. Vamorolone is a recently approved bone-sparing corticosteroid that has been shown to have similar efficacy as prednisone but does not cause growth failure. The study included a 24-week Period 1 (placebo, prednisone [0.75 mg/kg/day], vamorolone [6 mg/kg/day]), and a 24-week Period 2 where placebo and vamorolone groups crossed over to vamorolone. Clinical laboratory measures of ALP, osteocalcin, P1NP, and CTX1 showed significant reductions with prednisone, but were unchanged by vamorolone treatment or placebo. Proteomics studies of serum proteins reduced by prednisone, but not vamorolone or placebo, identified 10 proteins where mutations in the corresponding genes are known to cause genetic disorders of cartilage and/or bone (collagens [COL2A1, Chondrocalcin, COL6A1, COL9A1, COL10A1, COL11A2], aggrecan core protein [ACAN], biglycan [BGN], osteopetrosis-associated transmembrane protein 1 [OSTM1], and noggin [NOG]). On transitioning from prednisone to vamorolone, all 10 biomarkers returned to baseline levels. Non-human (animal) studies have shown that traditional corticosteroids cause apoptosis of terminal hypertrophic chondrocytes associated with growth failure. Our clinical trial studies suggest that the 10 novel, corticosteroid-related biomarkers likely reflect the induction of apoptosis in terminal hypertrophic chondrocytes and osteoblasts by traditional corticosteroids. Vamorolone may spare chondrocytes and osteoblasts from this apoptosis, consistent with maintenance of normal growth in vamorolone-treated children.Trial registration The clinical trial registration (clinicaltrials.gov) is NCT03439670 ( https://www.clinicaltrials.gov/study/NCT03439670 ).