Fractures and Linear Growth in a Nationwide Cohort of Boys With Duchenne Muscular Dystrophy With and Without Glucocorticoid Treatment

Abstract

Based on studies with relatively small sample size, fragility fractures are commonly reported in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD). OBJECTIVE To determine the fracture burden and growth impairment in a large contemporary cohort of boys with DMD in the United Kingdom and in relation to GC regimen. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of fracture morbidity and growth from 832 boys with DMD in the UK NorthStar database (2006-2015), which systematically captures information from 23 participating centers. A total of 564 boys had more than 1 visit. No numbers of boys who refused were collected, but informal data from 2 centers in London and from Scotland show that refusal is very low. Data were analyzed between October 2006 and October 2015. MAIN OUTCOMES AND MEASURES Fracture incidence rate per 10 000 person-years was determined. Cox regression analysis was used to identify factors associated with first fracture. RESULTS Median age at baseline was 6.9 years (interquartile range, 4.9-7.2 years). At baseline, new fractures were reported in 7 of 564 participants (1.2%). During a median follow-up of 4 years (interquartile range, 2.0-6.0 years), incident fractures were reported in 156 of 564 participants (27.7%), corresponding to an overall fracture incidence rate of 682 per 10 000 person-years (95% CI, 579-798). The highest fracture incidence rate was observed in those treated with daily deflazacort at 1367 per 10 000 person-years (95% CI, 796-2188). After adjusting for age at last visit, mean hydrocortisone equivalent dose, mobility status, and bisphosphonate use prior to first fracture, boys treated with daily deflazacort had a 16.0-fold increased risk for first fracture (95% CI, 1.4-180.8; P = .03). Using adjusted regression models, change in height standard deviation scores was −1.6 SD lower (95% CI, −3.0 to −0.1; P = .03) in those treated with daily deflazacort compared with GC-naive boys, whereas there were no statistical differences in the other GC regimen. CONCLUSIONS AND RELEVANCE In this large group of boys with DMD with longitudinal data, we document a high fracture burden. Boys treated with daily deflazacort had the highest fracture incidence rate and the greatest degree of linear growth failure. Clinical trials of primary bone protective therapies and strategies to improve growth in boys with DMD are urgently needed, but stratification based on GC regimen may be necessary.

Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy

“…Comparison of deflazacort‐treated and prednisone‐treated patients showed reduced COL1A1 levels in deflazacort‐treated patients compared with prednisone treated ones. Interestingly, a recent report shows that treatment with deflazacort was associated with a higher number of vertebral fractures, shorter time to first fracture, and higher linear growth failure . Results of ongoing studies such as the FOR‐DMD study will potentially clarify the effect of these drugs and regimes on bone health and whether events are associated with or predicted by COL1A1 levels in blood.…”

Glucocorticoid-Induced Osteoporosis: Why Kids Are Different

“…VF in children are rare in the absence of traumatic injury (21), and rates vary according to their method of detection. The highest frequencies of VF in secondary osteoporosis occur in boys with GC-treated DMD, where the VF prevalence is >50% (35), and the cumulative incidence is 28% over a median followup of 4 years from GC initiation (36). Children with leukemia, typically on intermittent GC therapy, have a VF prevalence of 16% at the time of diagnosis (3), and a cumulative incidence of 33% up to 6 years following diagnosis (20).…”

Effects of Bisphosphonate Therapy on Bone Mineral Density in Boys with Duchenne Muscular Dystrophy

“…16,17 Notably, a recent study by Joseph and colleagues demonstrated that boys with DMD treated with daily deflazacort had 16-fold increased risk for first fracture. 18 Bisphosphonates are widely used in the treatment of childhood osteoporosis and fragility fractures. 19 Several studies have demonstrated reduced frequency of fragility fractures and improved BMD after bisphosphonate therapy in pediatric patients with osteogenesis imperfecta and osteoporosis.…”

“…Notably, a recent study by Joseph and colleagues demonstrated that boys with DMD treated with daily deflazacort had 16-fold increased risk for first fracture. 18 …”