Anti-RANKL Therapy Prevents Glucocorticoid-Induced Bone Loss and Promotes Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy.

Bisphosphonates prevent bone loss in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD) and are recommended as standard of care. Targeting receptor activator of nuclear factor kappa-B ligand (RANKL) may have advantages in DMD by ameliorating dystrophic skeletal muscle function in addition to their bone anti-resorptive properties. However, the potential effects of anti-RANKL treatment upon discontinuation in GC-induced animal models of DMD are unknown and need further investigation prior to exploration in the clinical research setting. In the first study, the effects of anti-RANKL and deflazacort (DFZ) on dystrophic skeletal muscle function and bone microstructure were assessed in mdx mice treated with DFZ or anti-RANKL, or both for 8 weeks. Anti-RANKL and DFZ improved grip force performance of mdx mice but an additive effect was not noted. However, anti-RANKL but not DFZ improved ex vivo contractile properties of dystrophic muscles. This functional improvement was associated with a reduction in muscle damage and fibrosis, and inflammatory cell number. Anti-RANKL treatment, with or without DFZ, also improved trabecular bone structure of mdx mice. In a second study, intravenous zoledronate (Zol) administration (1 or 2 doses) following 2 months of discontinuation of anti-RANKL treatment was mostly required to record an improvement in bone microarchitecture and biomechanical properties in DFZ-treated mdx mice. In conclusion, the ability of anti-RANKL therapy to restore muscle function has profound implications for DMD patients as it offers the possibility of improving skeletal muscle function without the steroid-related skeletal side effects.

Cataract, abnormal electroretinogram and visual evoked potentials in a child with SMA-LED2 - extending the phenotype.

This case report describes a girl who presented antenatal arthrogryposis and postnatal hypotonia, generalized and respiratory weakness, joint deformities particularly affecting the lower limbs and poor swallow. By 5 months, cataracts, abnormal electroretinograms, visual evoked potentials (VEPs) and global developmental impairments were recognized. No causative variants were identified on targeted gene panels. After her unexpected death at 11 months, gene-agnostic trio whole exome sequencing revealed a likely pathogenic de novo BICD2 missense variant, NM_001003800.1, c.593T>C, p.(Leu198Pro), confirming the diagnosis of spinal muscular atrophy lower extremity predominant type 2 (SMA-LED2). We propose that cataract, abnormal electroretinograms and VEPs are novel features of SMA-LED2.

3T-MRI-based age, sex and site-specific markers of musculoskeletal health in healthy children and young adults.

Objective: The aim of this study is to investigate the role of 3T-MRI in assessing musculoskeletal health in children and young people. Design: Bone, muscle and bone marrow imaging was performed in 161 healthy participants with a median age of 15.0 years (range, 8.0, 30.0). Methods: Detailed assessment of bone microarchitecture (constructive interference in the steady state (CISS) sequence, voxel size 0.2 × 0.2 × 0.4 mm3), bone geometry (T1-weighted turbo spin echo (TSE) sequence, voxel size 0.4 × 0.4 × 2 mm3) and bone marrow (1H-MRS, point resolved spectroscopy sequence (PRESS) (single voxel size 20 × 20 × 20 mm3) size and muscle adiposity (Dixon, voxel size 1.1 × 1.1 × 2 mm3). Results: There was an inverse association of apparent bone volume/total volume (appBV/TV) with age (r = -0.5, P < 0.0005). Cortical area, endosteal and periosteal circumferences and muscle cross-sectional area showed a positive association to age (r > 0.49, P < 0.0001). In those over 17 years of age, these parameters were also higher in males than females (P < 0.05). This sex difference was also evident for appBV/TV and bone marrow adiposity (BMA) in the older participants (P < 0.05). AppBV/TV showed a negative correlation with BMA (r = -0.22, P = 0.01) which also showed an association with muscle adiposity (r = 0.24, P = 0.04). Cortical geometric parameters were highly correlated with muscle area (r > 0.57, P < 0.01). Conclusions: In addition to providing deep insight into the normal relationships between bone, fat and muscle in young people, these novel data emphasize the role of MRI as a non-invasive method for performing a comprehensive and integrated assessment of musculoskeletal health in the growing skeleton.

Observer Agreement of Vertebral Fracture Grading Using Dual Energy Absorptiometry Vertebral Fracture Assessment in Duchenne Muscular Dystrophy.

Routine screening of the spine for vertebral fracture is recommended in the recent international standards of care for boys with Duchenne muscular dystrophy (DMD). Recent international consensus endorses the use of dual energy absorptiometry vertebral fracture assessment for identification of vertebral fractures in children, which could be used instead of spine radiographs. This study aims to evaluate the inter-observer agreement for vertebral fracture classification in boys with DMD, and the impact on clinical management. Dual energy absorptiometry vertebral fracture assessment and morphometric analysis in 39 boys was performed by a reader with no prior experience (R1) and 2 readers with experience (R2 and R3). Inter-observer concordance of vertebral fracture grading comparing R1 with R2 and R3 was substantial (Kappa 0.66, 95% CI 0.56, 0.76). Concordance between R2 and R3 was almost perfect (Kappa 0.93, 95% CI 0.89, 0.97) which did not lead to differences in clinical management. Grading by R1 in comparison to R2 and R3 would have led to change in management of 5/39 boys (13%), according to recent standards of care guidance. Structured education programme on identification of vertebral fractures should be explored to ensure consistency of reporting of this important health outcome measure in DMD.

A survey of the feasibility of developing osteoporosis clinical trials in Duchenne muscular dystrophy: Survey of the opinion of young people with Duchenne muscular dystrophy, families and clinicians.

BACKGROUND/AIMS: Given the extent of osteoporosis in people with Duchenne muscular dystrophy treated with glucocorticoids and the limited evidence of bone-protective therapies, clinical trials are needed. We conducted surveys to obtain the opinion of young people with Duchenne muscular dystrophy, parents/guardians and neuromuscular clinicians on the feasibility of osteoporosis clinical trials in this population. METHODS: Online surveys were sent to three groups: (a) people with a confirmed diagnosis of Duchenne muscular dystrophy (≥14 years), (b) parents and guardians and (c) neuromuscular clinicians in the UK NorthStar Clinical Network. Surveys (a) and (b) were distributed via the UK Duchenne muscular dystrophy Registry. RESULTS: Survey respondents included 52 people with Duchenne muscular dystrophy with a median age of 17 years (range: 14, 40) and 183 parents/guardians. Fourteen out of 23 (61%) NorthStar centres responded. Of the 52 people with Duchenne muscular dystrophy, 13 (25%) were very concerned about their bone health and 21 (40%) were slightly concerned. Of the 183 parents/guardians, 75 (41%) were very concerned about their son's bone health and 90 (49%) were slightly concerned. Fractures and quality of life were the top two main outcome measures identified by people with Duchenne muscular dystrophy. Fractures and bone density were the top two main outcome measures identified by parents/guardians and neuromuscular clinicians. Thirty percent of people with Duchenne muscular dystrophy and 40% of parents/guardians would not take part if an osteoporosis trial involved a placebo that was administered parenterally. Only 2 of the 14 NorthStar centres (14%) would enrol people with Duchenne muscular dystrophy if a parenteral placebo was used in an osteoporosis trial in Duchenne muscular dystrophy. CONCLUSION: There is great awareness of bone health and the need for bone-protective trials among people with Duchenne muscular dystrophy and their carers. However, a proportion of people with Duchenne muscular dystrophy and parents are reluctant to participate in a placebo-controlled osteoporosis trial that included a parenteral therapy. A larger proportion of health care experts are unwilling to enrol their patients in such a trial. Our finding is relevant for the design of bone-protective studies in Duchenne muscular dystrophy.

Fractures and Linear Growth in a Nationwide Cohort of Boys With Duchenne Muscular Dystrophy With and Without Glucocorticoid Treatment: Results From the UK NorthStar Database.

Importance: 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.

Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy.

We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI - 6.1, - 0.66; p = 0.016). LL in DMD was 7.3 cm lower (95% CI - 11.2, - 3.4; p < 0.0001). SH:LL of boys with DMD was higher by 0.08 (95% CI 0.04, 0.12; p < 0.0001). Femur length in DMD was 2.4 cm lower (95% CI - 4.6, - 0.12; p = 0.04), whereas tibial length in DMD was 4.8 cm lower (95% CI - 6.7, - 2.9; p < 0.0001). SH:LL was not associated with duration of glucocorticoid use (SH:LL ß = 0.003, 95% CI - 0.01 to 0.002, p = 0.72).Conclusion: Glucocorticoid-treated boys with DMD exhibit skeletal disproportion with relatively shorter leg length and more marked reduction of distal long bones. As glucocorticoid excess is not associated with such disproportion, our findings raise the possibility of an intrinsic disorder of growth in DMD. What is Known • Severe growth impairment and short stature are commonly observed in boys with Duchenne muscular dystrophy (DMD), especially those treated with long-term glucocorticoids (GC). • In other groups of children with chronic conditions and/or disorders of puberty, skeletal disproportion with lower spinal length has been reported. What is New • Growth impairment in GC-treated boys with DMD was associated with skeletal disproportion in relation to age, with lower limbs and distal long bones affected to a greater degree.

Fractures and bone health monitoring in boys with Duchenne muscular dystrophy managed within the Scottish Muscle Network.

There are limited reports of radiologically confirmed fractures and bone health monitoring in with Duchenne muscular dystrophy. We performed a retrospective study of 91 boys, with a median age of 11.0 years, who are currently managed in Scotland with the aim to assess the frequency of radiologically confirmed fractures and report on bone health monitoring in relation to International Care Consensus Guidance. Of these boys, 59 (65%) were receiving glucocorticoid (GC) therapy and 23 (25%) had received previous treatment. Of those currently on GC, 37 (63%) had an assessment of bone mineral density and none had routine imaging for vertebral fractures during the study period. Of the 91 boys, 44 (48%) had sustained at least one symptomatic radiographically confirmed fracture. The probability of sustaining a first symptomatic fracture was 50% by 12.8 years old (95%CI: 12.1, 13.6). The most common sites for non-vertebral fracture were the femur and tibia. In this review of boys with DMD, almost half had sustained at least one radiologically confirmed symptomatic fracture. There is a need for standardized bone health monitoring in DMD that includes routine imaging of the spine to identify vertebral fractures, given the persistence of insult to the skeleton in these boys.