Combined growth hormone and insulin-like growth factor-1 rescues growth retardation in glucocorticoid-treated mdxmice but does not prevent osteopenia.

Claire L Wood,S Faisal Ahmed,Colin Farquharson,Rob Van ‘T Hof,Sze C Wong,Volker Straub,Scott Dillon

doi:10.1530/joe-21-0388

Abstract

Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence, an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. A 5-week-old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4 weeks and then compared to control mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, P < 0.05 compared to control). There was no improvement in bone microarchitecture (assessed by micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (Serum procollagen 1 intact N-terminal propeptide (P1NP), alpha C-terminal telopeptide (αCTX)) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD.

Highlights

Duchenne muscular dystrophy (DMD) affects 1 in 4000 live male births and is a severe and fatal disease (Crisafulli et al 2020) caused by mutations in the DMD gene at 21p on the X chromosome.The reduction or loss of dystrophin protein weakens the sarcolemmal membrane and results in progressive replacement of muscle fibres by fat and fibrous tissue (Deconinck & Dan 2007).Glucocorticoids (GC) are currently the mainstay of treatment in DMD and are an established pharmacological intervention proven to stabilise muscle strength for a finite period of time (Manzur et al 2008; Moxley et al 2010; Birnkrant et al 2018)
Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment
In contrast to the BW data, the administration of Growth hormone (GH) and IGF-1 was sufficient to rescue both crown-to-rump length and tail length growth retardation caused by GC; mean crown-to-rump length gain of 1.35 ± 0.45 cm (GH +IGF-1 treated) v 0.64 ± 0.30 cm and tail length gain of 0.95 ± 0.40 cm (GH+IGF-1 treated) v 0.32 ±

Summary

Introduction

Glucocorticoids (GC) are currently the mainstay of treatment in DMD and are an established pharmacological intervention proven to stabilise muscle strength for a finite period of time (Manzur et al 2008; Moxley et al 2010; Birnkrant et al 2018). The side-effects of GC, are well recognised, with growth retardation and bone fragility being extremely common. There remains limited effective therapy for management of poor growth and osteoporosis in these boys. Linear bone growth is known to be a driver for improvements in bone health in children. Impaired osteoblast function has been described in both X-linked muscular dystrophy (mdx) mice and patients with DMD (Rufo et al 2011). For that reason an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and requires further exploration

Objectives

Methods

Results

Conclusion