Care and treatment in Duchenne muscular dystrophy is evolving with improved treatments and promising therapies on the horizon. Parents and young men need to be proactive about care, to understand what to do, what can be done and the appropriate time for intervention. Risk/benefit analysis must be thoroughly and carefully evaluated. It is our responsibility as a community to act as advocates for our sons in order to improve current therapies, to address gaps in care, and to accelerate the development new treatments and one day, a cure.
The “Care Considerations” document is expected to be published in “LANCET” in the January and February issue. Using the Rand method, this document has been written to serve as a guide for optimal care. For some of you, there will be no surprises. The relevance of the document is to set standards for boys/young men and their parents all over the world, hopefully improving care in areas where knowledge and expertise is limited.
In the area of use of steroids in Duchenne, steroids are considered ‘gold standard’ but there is no consensus on the best regimen or timing of the intervention. The Care Considerations recommendations for intervention suggest a steroid regimen should be started when there is a plateau in strength. There are significant variations in the field with some physicians recommending a more aggressive approach. The document is not an endpoint, rather a beginning, setting the stage for what we know about care today and will be updated as new knowledge and therapies become available.
While steroids are now widely used, there is an urgent need to address the side effects of chronic steroid use. United Parent Projects Muscular Dystrophy (UPPMD) – is committed to work with experts to fill these gaps in care; to understand the issues and concerns; and to work with clinicians and subspecialists to understand what we know and what we will need to know and do in order to improve care. UPPMD members and Tony Huynh (Endocrinologist from Australia, son with Duchenne) organized a workshop to promote dialogue and discussion of Endocrine issues in Duchenne. The meeting was held October 28 and 29 in Florence, Italy.
Endocrine issues in Duchenne include:
o Bone Health – Bone Density in Duchenne is abnormal at diagnosis. Steroids have additional negative effect on bone density.
o Growth Delay – Boys with Duchenne are shorter than their healthy peers. Steroids further impact this growth delay.
o Delayed Puberty – Delayed puberty or complete suppression of puberty is seen with steroid use.
o Insulin Resistance – Chronic steroid use can lead to weigh gain and insulin resistance.
Putting the issues on the table:
Initial Question – what would you do if your 13 y/o son arrived home from his school, in tears, because he looked so different from his peers – shorter, pre-pubescent, facial distortion and overweight. What would you do?
As a community, it is unacceptable to put that question on hold for several years while clinical trials are developed and even more years before the data is available and decisions made. While we appreciate and agree that evidence based medicine is the gold standard, is there a middle ground, an approach we might take to work together to sort out some of these questions in a timely to help this generation of boys in an effort to limit side effects of chronic steroid use, improve self-esteem, and quality of life?
Duchenne is complex multi-system condition and answers are not straightforward. We have learned a great deal about mutations and the in-frame/out-of-frame rule, and while the rule works some of the time, not all boys follow the rules. There are genetic modifiers that influence and alter progression. There are significant challenges to testing compounds in the Duchenne population and proving benefit (or not).
The initial discussion of the UPPMD workshop on Endocrine issues focused on steroid dose. There was general agreement on the dose .75mg/kg Prednisone and .9mg/kg Deflazacort. Some of the physicians adjust dose as size/weight increase, while others make no changes to the initial recommended dose. While there is no comparative data, some physicians suggested their patients have less side effects when the dose is not adjusted (increased), rather the initial dose was maintained over time.
SESSION 1 – GROWTH
In many presentations on use of steroids, physicians suggest ‘shorter is better’. Diana Escolar used principles of physics on force and resistance to demonstrate ‘shorter is better’ in terms of muscle strength. But the question is not simple. Is shorter better psychologically? Are the boys (not their parents) ok with short stature? Boys with Duchenne are already destined to be shorter than their healthy peers. Publications suggest that Duchenne boys have normal weight and height, but delays in growth begin during their first years of life. Craig McDonald’s paper suggested the median height of Duchenne is significantly less (<50th percentile) than their healthy peers by age 10. The question remains – Is short stature a detriment in Duchenne? There is no data to support functional or psychological detriment of short stature in Duchenne and there is very little information available, only several case reports. Based on the available data, no recommendations regarding treatments can be made for treating short stature in Duchenne.
Meilan Rutter discussed her experience in Cincinnati. To date, she has evaluated 30 boys with growth failure. The boys have been followed up for 6 months to 2 years. All are on long term steroids and the ages range from 9-17 years. 26 of the 29 boys had low or borderline GH levels. Using GH, the height/growth velocity increased from the rate of 1 cm/year to an average of 5 cm/year. Dr. Rutter suggested that this experience has NOT been completely analyzed, that more work is needed. The long term effect is not known.
• Evidence suggests that Duchenne does influence height and that short stature is not detrimental to function
• Data is lacking on actual psychological impact of height restriction due to steroids and interaction of other factors (cushionoid appearance, pubertal delay)
o Linear height is not trivial
o Standards need to be laid out and disseminated for measuring height
o National specific growth charts need to be used
o Need to determine how GH is to be measured.
Height data could be added to the current data collection natural history collaboration with Treat NMD and other groups.
If assessments of GH are possible could they be addressed as an add-on to the upcoming Treat NMD steroid trial?
It was generally thought that a retrospective look may have quality issues and may not provide useful information. The participants recommended Dr. Rutter’s data be thoroughly analyzed and may provide a starting point.
o GH data need to be assessed both in respect to height gain and strength/function
o Timing of intervention need to be determine
o Concern that this intervention will necessarily be individualized rather than a standardized treatment
o Pilot data may be interesting/informative from Cincinnati cohort already treated
o TACT review of potential for trial (June meeting)
SESSION 2 – PUBERTY
High dose steroids result in delayed or arrested puberty. Cincinnati Children’s has 486 boys in their database. 60 boys ages 13 and older were given pubertal exams and tested for testosterone levels. 16 of these young men were not included in the case study because they were adults and on low or an intermittent dose of steroids. 43/44 of these young men had no evidence of puberty. Their testosterone levels were undetectable. All of the young men had small penises. 15 of the boys have been treated with 1/month injections of testosterone. By adulthood, young men would be on testosterone regimens every two weeks. In some cases AndroGel (topical testosterone) was used.
Young men treated with testosterone have experienced changes related to puberty – increased facial hair, increased size of penis, changes in facial distortion.
• Pubertal delay or complete suppression of puberty is seen with prolonged steroid use.
• Testosterone replacement is possible.
• No concerns expressed with testosterone replacement.
• Guidelines are needed to include assessments and timing of interventions.
• Testosterone (AndroGel)
SESSION 3 – BONE HEALTH
Published evidence suggests, children with Duchenne have an increased risk of fracture which is exacerbated by chronic steroids use. C. McDonald’s paper suggested that Duchenne boys who do not take steroids have a high incidence of fracture. W. King’s paper noted 32% have vertebral fractures in steroid group and an increased risk (2.6X) of long bone fractures. Bothwell predicted a 75% risk of fracture following 100 months of steroids use.
The effect of steroids and Duchenne on bone are complex. While steroids affect the rate of bone growth and therefore bone mass, immobility adds to the reduction in bone mass. In addition, it is difficult to establish consensus/clear guidance on how to measure bone mineral density and how to interpret results. Boys with Duchenne, even those who do not use steroids, have low bone mineral density and the bone mineral content does not increase normally with age.
Bisphosphonate treatment is indicated when a vertebral fracture is present to reduce acute pain and to preserve bone density in the future. There is no agreement on prophylactic treatment.
UK consensus statement applied across 19 centers recommends DXA scans annually at the start of steroids and Vitamin D levels. The statement includes the recommendation to treat vertebral fractures with IV Bisphosphonate.
Kate Bushby recommends Risedronate 35mg; calcium 500mg. and Vitamin D 400 U. to her patients on daily steroids. Side effects are monitored to include dental prophylactics, urinary calcium/creatine rati, and DXA every 12 months.
Bone health in Duchenne is a challenge. Challenges include:
• Cumulative dose of (at least daily) steroid regimes to have an impact on bone health and can lead to painful vertebral fractures which can limit ambulation.
• Can we optimize steroid regimes to minimize risks while maintaining functional benefit?
• Can we decide on a rational regimen for prophylaxis?
• Does this require Randomized Clinical Trials (RCT)?
• Is it acceptable to provide interim guidance as the burden of steroid treatment in the community increases?
• Bone health is complex, the elements include: density/strength/quality.
• DXA considered gold standard for measuring Becker muscular dystrophy.
• In Duchenne, the increased risk of fracture is 5% per year
• Pediatric position 2007 – only Z score should be considered. Is this sufficient in Duchenne?
• Relationship emerging between DXA data and fracture risk in children.
• There is increasing experience of bisphosphonates in children and in the Duchenne population in particular
• Randomized Clinical Trial (RCT) is planned for trial in Australia. Are others needed?
• Need guidelines for assessment and prophylaxis.
• Vitamin D needs to be measured and supplemented.
• Calcium, Vitamin D
SESSION 4 – WEIGHT GAIN
The impact of increased weight in Duchenne includes carbohydrate intolerance, diabetes, heart disease, impaired lung function, decreased mobility, further weight gain, increased osteoporosis, poor self-image, increased caregiver burden, and quality of life for everyone. While it is easy to say ‘calories in, calories out’, the issue is complex. Clinical evaluation on growth must be evaluated. This should be accompanied by dietary evaluation and screening labs (fasting glucose, including HbA1c) and in some cases GTT. Options include altering steroid dose and regimen, improved diet (exercise), and medications. Metformin is an insulin sensitizing agent that improves weight and insulin resistance in patients with diabetes and excessive weight. Recommended dose is 1000-2000mg/day.
In Cincinnati, 15 boys have been treated with Metformin. Most had normal glucoses. ALL had insulin resistance. Metformin was used as an adjunctive treatment in addition to diet. 13/15 boys lost weight with improved self-esteem and quality of life.
• Weight gain
• Dietary Evaluation
• Screening blood tests
• Need to establish threshold for GTT
• Diet/Education – Consider Weight Watchers or similar
• 75-80% normal intake for ambulant boys
• Non-ambulant 60-75%
• Consider Metformin for those with proven insulin resistance and extreme weight gain.
• Are there straightforward guidelines from other specialties or adult practice?
STOPPING STEROIDS – Steroid Withdrawal
The main effect of glucocortoid is suppression of adrenal glands. This suppression results in feedback to the pituitary and hypothalamus and results in decreased CRH and ACTH). High doses or too much glucocorticoid is associated with cushionoid syndrome and chronic steroid administration results in hypothalamus – pituitary adrenal suppression, which is dose, duration, and mode dependent. Withdrawal from a steroid regimen has to be done in consultation with your physician.
Recommended way to withdraw from steroid:
1. Reduce dose by 25% on a 1-2 wk, basis.
2. When at physiological dose switch to equivalent dose of hydrocortisone 12mg/m2/day.
3. Decrease by 2 ½ mg/wk.
4. Emergency care guidelines in place.
One KEY point is that the circadian rhythm recovers first.
• Stress testing after a year of steroids.
• Need more data in this specific condition (antibody response to immunization, stress response).
• Emergency guidelines need to be reinforced.
Participants in the meeting:
Tony Hunyh (Endocrinologist, Australia)
Meilan Rutter (Endocrinologist, USA)
Maria Luisa Bianchi (Endocrinologist, Italy)
Peter Hindemarsh (Endocrinologist, UK)
Kate Bushby (Clinical Genetics, Newcastle)
Kevin Flanigan (Neurologist, USA)
Doug Biggar (Pediatrician, Canada)
Brian Tseng (Neurologist, USA)
Diana Escolar (Neurologist, USA)
Larry Markham (Cardiologist, USA)
Chris Condin (Anthropologist, Canada)