Scientists now have evidence to explain why treatment with the corticosteroid prednisone — but not the newer steroid Agamree (vamorolone) — drives bone loss in young boys with Duchenne muscular dystrophy (DMD) and may slow their growth.
Using data from a clinical trial, the researchers found that prednisone, a standard treatment for DMD, significantly lowered blood levels of several proteins linked to bone and cartilage growth among boys with Duchenne. The so-called dissociative steroid Agamree, meanwhile, had no such effects.
According to the researchers, “prednisone, [but] not [Agamree], suppresses … bone and cartilage biomarkers associated with growth failure” in boys with DMD.
Further, once the boys switched from the older treatment to the newer one, as per the trial protocol, all of the assessed proteins returned to normal levels, the data showed.
The study, “Prednisone, not vamorolone, suppresses novel serum bone and cartilage biomarkers associated with growth failure in children with Duchenne muscular dystrophy,” was published in the journal Scientific Reports. Three study authors are employed by Reveragen Biopharma, which originally developed Agamree, while two others work for Santhera, which holds marketing rights to the drug.
DMD, the most common type of muscular dystrophy, is marked by progressive muscle weakness and wasting, mostly in boys.
Corticosteroids such as prednisone are a standard treatment for DMD because they help reduce inflammation and preserve muscle strength. However, these drugs are also known to cause bone thinning and slowed growth in children.
Agamree is a newer corticosteroid that’s structurally different from prednisone and approved for people with DMD, ages 2 and older. It has been shown to confer similar benefits for muscle strength in DMD as prednisone, but without the same growth-related side effects.
Getting to the bottom of differences in steroid treatment
In this study, researchers across two continents set out to explain the biological difference between prednisone and Agamree. To that end, the scientists — from North America and Europe — examined biomarker data collected during the Phase 2 VISION-DMD trial (NCT03439670).
That study enrolled 121 boys with DMD who could walk, ages 4-6. The participants received oral Agamree (2 or 6 mg/kg), prednisone (0.75 mg/kg), or a placebo once daily for six months. All were then treated with Agamree for another six months. Among them, 102 boys had blood samples collected at multiple time points for analysis.
The team first measured commonly used biomarkers of bone turnover — proteins released as bone tissue is built up and broken down. These were alkaline phosphatase (ALP), osteocalcin, procollagen type I N-propeptide (P1NP), and C-telopeptide of type I collagen (CTX1).
Blood tests revealed that prednisone treatment reduced all four biomarkers by 24% or more relative to the placebo, whereas Agamree showed no change. ALP specifically dropped by about 39% during prednisone treatment. After participants stopped prednisone and completed a four-week taper period before starting Agamree, all four biomarkers recovered close to their starting (baseline) levels.
To identify additional biomarkers, the researchers used a technique that measured the levels of thousands of proteins in blood at once. Here, 10 proteins associated with known genetic bone or cartilage conditions were reduced by prednisone but not by Agamree or the placebo. The reductions were as much as 59% relative to the placebo. Each of these 10 biomarkers returned to baseline levels once participants switched from prednisone to Agamree.
Newer steroid treatment does not affect growth proteins
The team noted that several of these proteins are produced by chondrocytes, the cartilage cells found in the growth plate, which is the region near the ends of bones that lengthen as they grow.
For example, COL10A1 is a known marker of a mature form of these cells found specifically in actively growing bone. Reduced COL10A1 was also seen in boys with DMD compared with healthy children before treatment, and it dropped further with prednisone, the researchers noted.
The team suggested that “COL10A1 testing might be employed for monitoring growth in infants and children with genetic and acquired growth disorders, and might also monitor interventions that seek to improve growth velocity.”
Lastly, the researchers investigated how biomarker changes related to changes in height. Eight of 12 prednisone-treated patients clustered together, showing the greatest reductions in height and biomarkers. Change in height was most closely associated with change in ALP levels. Three of the remaining four prednisone-treated participants showed reductions in height, but their bone biomarker stability was comparable to that of the Agamree group.
Cross-over from prednisone to [Agamree use] restored all biomarkers to pre-treatment (placebo) levels.
The team noted that prednisone and Agamree led to similar improvements in motor function during the trial, which rules out differences in physical activity or motor improvement as an explanation for the bone biomarker results.
To understand the findings, the scientists suggested that traditional corticosteroids induced programmed cell death in chondrocytes and bone growth cells called osteoblasts. Further, Agamree may spare these cells from that process, resulting in normal growth in children treated with that newer drug.
“We report the discovery of novel serum [blood] protein biomarkers … that are differentially regulated by prednisone and [Agamree] in boys with DMD,” the researchers concluded. “[Agamree] did not result in significant changes of these growth-related biomarkers, and cross-over from prednisone to [Agamree] restored all biomarkers to pre-treatment (placebo) levels.”
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