Pediatrics · Medical Literature
Prednisone, not vamorolone, suppresses novel serum bone and cartilage biomarkers associated with growth failure in children with Duchenne muscular dystrophy.
Abstract
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 ).
Clinical relevance
In young children with Duchenne muscular dystrophy (DMD) treated with standard-dose corticosteroids, does vamorolone—compared with prednisone and placebo—differentially suppress serum bone and cartilage biomarkers, and can proteomic methods identify novel biomarker proteins mechanistically linked to prednisone-associated growth failure? __SNAPSHOT__ {"studyDesign":"Longitudinal proteomic substudy of a randomized, double-blind, placebo- and prednisone-controlled phase 2b trial (VISION-DMD; VBP15-004; NCT03439670) with a crossover extension","setting":"International multicenter trial; specific institutions not reported in the abstract","sampleSize":"n=121 randomized in the parent trial (4 arms); proteomic subsample size not reported in the available abstract excerpt","population":"Steroid-naive boys with genetically confirmed Duchenne muscular dystrophy, aged 4 to <7 years (mean age approximately 5.4 years), enrolled in the VISION-DMD trial","intervention":"Vamorolone 6 mg/kg/day (Period 1 and Period 2); the abstract also references vamorolone as the crossover treatment for placebo and prednisone groups in Period 2","comparator":"Prednisone 0.75 mg/kg/day (Period 1 only, then crossed over to vamorolone in Period 2); placebo (Period 1 only, then crossed over to vamorolone in Period 2)","primaryOutcome":"Identification of serum biomarkers of prednisone-related perturbations of bone and/or cartilage metabolism associated with growth failure, using longitudinal proteomic methods (SomaScan platform); clinical laboratory measures of ALP, osteocalcin, P1NP, and CTX1 served as corroborative conventional biomarkers","followUp":"48 weeks total (24-week Period 1 + 24-week Period 2)","fundingSource":"National Institutes of Health (NINDS) and European Commission Horizon 2020, per the parent trial; ReveraGen BioPharma involvement noted; full funding details for this specific substudy not reported in the available abstract"}
Key findings
Standard clinical laboratory bone biomarkers—alkaline phosphatase (ALP), osteocalcin, procollagen type I N-terminal propeptide (P1NP), and C-terminal telopeptide of type I collagen (CTX1)—showed statistically significant reductions with prednisone treatment but were unchanged in the vamorolone and placebo groups. Specific p-values and effect sizes for these comparisons are not reported in the available abstract. Serum proteomic analysis (method not fully specified in the abstract excerpt, likely SomaScan) identified 10 serum proteins that were selectively suppressed by prednisone but not by vamorolone or placebo; the abstract excerpt indicates that mutations in the genes encoding these 10 proteins are associated with known bone and/or cartilage disorders linked to growth failure, providing mechanistic biological plausibility. Protein names, fold changes, confidence intervals, and adjusted p-values for individual proteins are not reported in the available abstract excerpt. Height percentile declined with prednisone but not with vamorolone in the parent trial (LSM difference prednisone vs. vamorolone 6 mg/kg/day: −5.01 percentile points; p=0.02), consistent with the bone-sparing biomarker findings. A prior 48-week analysis demonstrated reversal of prednisone-induced bone biomarker suppression after crossover to vamorolone. NNT and NNH cannot be calculated from the available data.
Practice implications
This study establishes, using both conventional clinical laboratory measures and high-throughput serum proteomics, that prednisone at standard DMD dosing (0.75 mg/kg/day) suppresses multiple biomarkers of bone formation and cartilage metabolism in young children with DMD, while vamorolone (6 mg/kg/day) does not. The identification of 10 proteomic candidates whose gene mutations cause growth-related skeletal disorders adds mechanistic depth to the bone-sparing profile of vamorolone and suggests potential future biomarkers for monitoring corticosteroid-related bone toxicity. The study does NOT establish: (1) whether suppression of these biomarkers translates into clinically meaningful differences in fracture rates, bone mineral density, or final adult height; (2) whether the identified proteins are causally linked to growth failure or are merely epiphenomenal markers; (3) how findings apply beyond the narrow 4– 80% White in the parent trial), limiting generalizability across populations.,Involvement of ReveraGen BioPharma (vamorolone developer) in study conduct and authorship represents a potential conflict of interest that may influence interpretation, though government funding mitigates this concern partially.,Surrogate biomarker endpoints: changes in ALP, osteocalcin, P1NP, and CTX1 are established markers of bone turnover but are not validated as surrogates for fracture risk or growth in DMD specifically.,The crossover design in Period 2 precludes blinded comparison of prednisone vs. vamorolone beyond 24 weeks. __BOTTOM_LINE_CATEGORY__ confirmatory __BOTTOM_LINE__ This proteomic substudy of the VISION-DMD phase 2b trial demonstrates that prednisone, but not vamorolone, suppresses established serum bone turnover biomarkers (ALP, osteocalcin, P1NP, CTX1) and a novel panel of 10 proteomic candidates mechanistically linked to skeletal growth disorders in young boys with DMD. These findings provide additional biological plausibility for vamorolone's bone-sparing clinical profile but are exploratory and require independent replication and long-term skeletal outcome data before they can serve as validated clinical monitoring tools. Clinicians treating DMD with corticosteroids should be aware that vamorolone's regulatory approval already reflects its superior bone and growth safety profile versus prednisone; this study deepens mechanistic understanding but does not independently change prescribing practice.