21st June 2019
St Virgil Conference Centre, Salzburg, Austria
On the 21st of June 2019 a symposium on muscle-bone interaction in Duchenne muscular dystrophy was organised by Dr. Jarod Wong (Developmental Endocrinology Research Group, University of Glasgow) and Dr. Michela Guglieri (John Walton Muscular Dystrophy Research Centre, Newcastle University), supported by an educational grant by Duchenne Parent Project Netherlands. The symposium was adopted as a pre-congress symposium of the 9thInternational Conference for Children’s Bone Health in Salzburg. The symposium was attended by approximately 90 clinicians and researchers in the bone and neuromuscular fields. Topics discussed were discussing the latest developments on the interactions between muscle and bones in DMD, recent updates in clinical care and avenues for future research.
“It is very important that the 2018 updated standards of care on bone monitoring and management for DMD are implemented” – Dr. Jarod Wong, symposium co-organizer stated. “However, research into preventing the first fracture in DMD, and finding better treatment for bone health after fractures are now needed. It is important that bone and muscle specialists work closely together, in conjunction with patient organizations”.
“We are very grateful to Duchenne Parent Project Netherlands for supporting this scientific symposium and a collaborative planning meeting on developing research in bone health for DMD”, said Dr. Michela Guglieri. “We have included some summary points from each speaker at this symposium to share with all patients”.
HIGHLIGHTS FROM SPEAKERS’ TALKS
DMD: A multi-system condition and importance of standards of care for clinical management
Prof. Günther Bernert, Austria
- Life expectancy of people with DMD has increased greatly over the last decade due to improved care in line with international standards of care, steroid treatment and assisted ventilation.
- Discussions with the family on type, dosing, regimen, effects and side effects of steroids should start early.
- A multi-disciplinary approach to care of people with DMD is needed and the 2018 updated standards of care cover many aspects that may impact on the health of boys and men with DMD.
Glucocorticoid treatment in DMD: Paediatric perspective
Prof. Nathalie Goemans, Belgium
- Steroids have been shown to slow down disease progression, preserve muscle function and increase life expectancy in people with DMD.
- Even though steroids have many side effects, such as weight gain, slow growth, delayed puberty and behavioural problems, the benefits outbalance the risks.
- Prednisolone and Deflazacort are the most used steroids for DMD, but there is still no clear evidence on which steroid regimen optimises muscle function with the fewest side effects.
Glucocorticoid treatment in DMD: Adult perspective
Dr. Ros Quinlivan, UK
- The number of adult men with DMD is increasing in recent years and the majority have been treated with steroids for more than ten years. Therefore, monitoring of these adult men needs attention in specialist clinics.
- Adult care for people with DMD maybe more fragmented than paediatric care. Better coordination and collaboration of care for adults with DMD is now needed.
- Many health issues can occur in adults with DMD, for example osteoporosis, diabetes, kidney problems and nutritional issues. The best way to monitor and manage these problems in adults with DMD remain unclear.
Therapeutic targets in DMD & overview of DMD treatment clinical trials
Dr. Michela Guglieri, UK
- Only two therapies targeting the loss of dystrophin are currently approved in America or Europe (Eteplirsen and Ataluren), but only for a small subset of people with DMD and their effects are limited.
- More than 80 clinical trials are currently ongoing, of which 50 are testing possible new medicines. Majority of the trials recruit paediatric, ambulatory boys.
- Many families and people with DMD are using commercially available compounds not under prescription, which is not always known by their clinicians. This may cause interactions with prescribed medications and families should be encouraged to be open with their clinicians.
The muscle-bone cross talk and implications for neuromuscular conditions
Prof. Frank Rauch, Canada
- Muscle and bone influence are very closely related- loading of the muscle on bones help to increase bone mass.
- In growing children, constant overload on the bones by muscle help bones to grow in length but also in width, leading to increased bone strength.
- In DMD, muscle wasting leads to a decreased load on the bone and this itself can lead to poor bone development during childhood.
Mechanism of glucocorticoid induced osteoporosis and lessons from adult trials
Prof. Mark Cooper, Australia
- Studies from adults using steroids in other conditions (not DMD) show that fracture risk is increased, even at much lower doses of steroids than used in DMD.
- Long term steroid use decreases the amount of bone being formed, and also reduces bone breakdown but to a lesser extent. These abnormalities lead to overall loss of bone tissue.
- In trials of adults taking steroids (not DMD), several medicines have been shown to improve bone health and reduce the number of fractures. However, some of these medicines, such as Teriparatide, may not be suitable for growing children.
Experimental models to study the effects of DMD & glucocorticoid on bone strength and growth
Prof. Colin Farquharson, UK
- Animal models are important to test new drugs before they are tested in humans. There are several animal models of DMD but all have limitations. In particular, the mdx mouse model has a less severe clinical course than boys with DMD.
- In contrast to DMD boys, DMD mice (without steroid treatment) show minimal growth and bone abnormalities. A novel model, the mdx:cmah-/- mouse, appeared to show a more severe muscle phenotype but the bone and growth pattern do not mimic the human condition and is therefore not a good model to test potential medicines to improve bone and growth in DMD.
- Mouse studies of DMD confirm that giving steroid (Prednisolone) can lead to poorer bone. This model can be used to test new medicines to improve bone before developing clinical trials in boys and men with DMD.
Osteoporosis management in DMD and updated standards of care 2018
Dr. Jarod Wong, UK
- Boys with DMD treated with steroids have smaller, weaker bones and poorer bone quality.
- Fractures are extremely common in DMD especially fractures of the spine (vertebral fracture) and are missed if routine imaging of the spine is not performed. This is now recommended in the 2018 updated standards of care.
- Treatment with bisphosphonates is recommended in the standards of care if moderate and severe vertebral fractures are identified even without back pain to prevent further deterioration of those fractures.
Identifying vertebral fractures and assessing fracture risk in DMD-Implementing the 2018 standards of care and developing research
Dr. Nicola Crabtree, UK
- Routine spine imaging to detect vertebral fracture is now recommended but images need to be interpreted carefully.
- Bone density scans are also part of monitoring bone health in DMD but may not accurately predict vertebral fractures in DMD
- The best way of monitoring and predicting fractures in boys with DMD is still unclear and more research is needed.
Puberty and growth management to improve bone health in DMD and updated standards of care 2018
Prof. Margaret Zacharin, Australia
- Delayed puberty is common in DMD, and mainly due to the long term use of high dose steroid.
- As a healthy boy progresses through puberty, bone size and strength increase by a large amount. This is particularly important in DMD, when the bones are smaller and weaker even in early to mid childhood.
- Using testosterone therapy when there is no sign of puberty in an adolescent boy with DMD (ideally, no later than age 14 years) is now recommended in the 2018 standards of care. It has positive psycho-social and emotional impact on the adolescent and may improve bone density.
Vibration therapy to improve muscle-bone in neuromuscular conditions
Dr. Ibrahim Duran, Germany
- Whole body vibration therapy maybe an option to improve bone health in DMD, given the close link between muscle and bone.
- Vibration therapy in conjunction with a rehabilitation programme can improve bone health in children with movement disorders and cerebral palsy.
- However, there are very limited number of studies of vibration therapy in DMD with small number of subjects.
Dissociative steroids in DMD: Impact on bone and endocrine axis
Dr. Laurie Conklin, USA
- Vamorolone is a steroidal compound that retains the beneficial effects of steroids, but reduces the side effects.
- Initial study results indicate improvements of muscle function, with less weight gain, no growth stunting and less impact on blood markers of bone health.
- A placebo-controlled blinded phase 2 trial is currently recruiting world-wide. In this study fracture outcome will studied.
Targeting Nuclear Factor Kappa-B with edasalonexent for muscle and bone health in DMD
Dr. Joanne Donovan, USA
- Edasalonexent is a non-steroidal drug, investigated as replacement for steroid which targets the pathway that impacts on inflammation in DMD.
- In animal studies, bone sparing effects were seen with the use of Edasalonexent.
- The first clinical trial show improved muscle function associated with normal growth patterns, with a larger randomized trial now recruiting internationally.
RANKL inhibition to target muscle and bone in DMD
Prof. Jérôme Frenette, Canada
- Muscle and bone share several common signalling pathways. The RANK/RANKL/OPG pathway is one of them, and this pathway can impact on inflammation in DMD.
- In animal models of DMD, inhibition of RANKL has positive effects on muscle function, heart and bone strength.
- Exploring the impact of drugs which inhibit RANKL on muscle function in DMD as part of research study should now be considered, as drugs which target RANKL (Denosumab) are already used to treat osteoporosis in elderly women and in some other children with rare forms of osteoporosis.
A critical appraisal of anti-resorptive and anabolic therapies to improve bone health in DMD
Prof. Leanne Ward, Canada
- Currently, the only bone protective medicine that is used routinely in clinical practise in children to treat osteoporosis is bisphosphonate.
- The use of bisphosphonate given via an infusion into the veins in DMD can help relieve vertebral fracture-associated back pain and lead to stabilization of those fractures.
- Medicines that increase the amount of bone formed may be more beneficial in DMD but such medicines are either not safe for use in children or not been tested yet. Research testing medicines that increase the amount of bone formed should be considered in the future for boys with DMD.
Update from European Neuromuscular Centre (ENMC) workshop on developing osteoporosis trials in DMD
Dr. Jarod Wong, UK
- Delegates (including patients and patient representatives) in the June 2018 ENMC workshop felt that research into preventing the first fracture; and comparing new medicines to treat osteoporosis after the first fracture with current treatment (bisphosphonate) are important research priorities in DMD.
- A survey conducted prior to the ENMC workshop showed that families and people with DMD are concerned about bone health and fractures.
- However, almost half of families and people with DMD would not be keen to take part in a bone health trial if it involves the possibility of being randomized to a group where placebo is administered as an infusion into the veins or via injection into the skin. The information of the opinion of families should be taken into consideration by researchers in the development of future bone protective trials.
Prepared by Ingrid Verhaart and Claire Wood, June 2019