Endocrine aspects of duchenne muscular dystrophy

Available online at www.sciencedirect.com Endocrine Aspects of Duchenne Muscular Dystrophy Maria Luisa Bianchi Doug Biggar , Kate Bushby , Alan D. Rogol a Bone Metabolism Unit, Istituto Auxologico Italiano IRCCS, Milano, Italy b Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, Ont., Canada c Institute of Human Genetics, International Centre for Life, Newcastle University, Newcastle Upon Tyne, UK d Riley Hospital for Children, Indianapolis, IN, University of Virginia, Charlottesville, VA, USA e Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA f Pediatric Neuromuscular Clinic, Division of Child Neurology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Received 24 October 2010; received in revised form 24 January 2011; accepted 2 February 2011 In the last few years, the remarkable expansion in clini- cal and therapeutic capabilities has changed the natural In October 2009, the United Parent Projects Muscular history of many chronic diseases starting in childhood, Dystrophy (UPPMD) organized the First Conference on with increased survival rates and increased numbers of sub- the Endocrine Aspects of Duchenne Muscular Dystrophy jects living for a much longer time, often into adulthood.
(DMD), as these topics had never been thoroughly dis- These changes have also been observed in DMD, for which cussed until then. Children and adolescents affected by corticosteroids (CS) are now widely used to slow the pro- DMD, and consequently their parents, are currently requiring increasing attention, because of the new clinical The counterpart of these positive medical achievements problems related to longer survival and long-term cortico- has been the appearance of treatment-related adverse steroid treatment. The conference was attended by 17 par- events with multiple organ involvement of a wide spectrum ticipants (8 from the USA; 2 each from Canada, Italy, and of severity. In the follow-up of boys with DMD, we are UK; 1 each from Australia, Germany, The Netherlands; of now confronting endocrine system issues never considered these, 5 were representatives of the United Parent Project, before (e.g. delayed puberty, short stature, obesity, osteo- and 12 were clinicians and researches from 12 different porosis, etc.). This increases the problems and needs of patients, and poses novel challenges to caregivers and phy- This first meeting was focused on what is known, which sicians. For this reason, there is an urgent need to create preliminary studies are ongoing, and what needs to be done collaborative teams of different specialists.
on four main topics: growth, puberty, weight gain and The first meeting concerning the endocrine aspects of DMD (Florence, Italy, October 2009) was a starting point This article is a summary of these four topics, with some to initiate dialogue on relevant issues and to increase the concluding remarks. It is a starting point to stimulate collaboration of neurologists with endocrinologists and attention, debate and specific studies on the endocrine chal- Dr. Brian Tseng presented the historical background ⇑ Corresponding author. Address: Bone Metabolism Unit, Istituto and clinical features of DMD, and underlined how sup- Auxologico Italiano IRCCS, via L. Ariosto, 13, 20145 Milano, Italy. Tel.: portive medical efforts have changed the prospective of +39 02 619112505; fax: +39 02 619112519.
these patients, offering a longer survival. Irrefutable evi- 0960-8966/$ - see front matter Ó 2011 Published by Elsevier B.V.
Please cite this article in press as: Bianchi ML et al., Endocrine Aspects of Duchenne Muscular Dystrophy, Neuromuscul Disord (2011), M.L. Bianchi et al. / Neuromuscular Disorders xxx (2011) xxx–xxx dence of this fact is the growing population of men with sium and body weight. However, in boys with DMD, DMD who are active, happy, social, educated and some hGH is suspected of playing a role in the pathogenesis of even working full-time. For this reason, the need of multi- the condition : with relatively high doses of rhGH disciplinary, interdisciplinary (coordinated) and transi- there are negative balances of sodium, potassium and tional (pediatric to adult medical care) strategies was sometimes phosphorus; none of the boys with DMD exhib- ited any anabolic responses to any dose of rhGH.
Dr. Doug Biggar reported that today, only CS (predni- There is some evidence suggesting that hGH could be sone and deflazacort) slow the progression of muscle weak- detrimental to muscle in subjects with DMD. However, ness in boys with DMD. Most agree that CS should be several trials with Mazindol, a weak inhibitor of hGH given daily to be most effective. He summarized the main secretion, did not show a positive effect on the course of benefits of long-term daily use of CS (improved skeletal muscle function decline Treatment strategies based muscle, cardiac and pulmonary functions, delayed onset on the physiology of hGH release are mainly theoretical of scoliosis and contractures, and preserved upper extrem- at this time, but there are several agents that have been ity function), and underlined that the side-effects of daily used in humans or can be tested in mdx mice.
CS on endocrine function are common and significant.
Dr. Meilan Rutter reported that short stature secondary Reporting his experience with deflazacort, he noted that to chronic CS in DMD boys may negatively impact psy- the side-effect profile with daily deflazacort might be less chosocial health, quality of life and clinical outcome. In than with daily prednisone, but nevertheless the side effects DMD, baseline height velocity and growth hormone test- are significant. The boys’ height velocity is slowed signifi- ing are typically normal in the absence of CS therapy .
cantly by 12–18 months after starting deflazacort, and by However, chronic CS therapy results in growth failure, 13–15 years of age, their height might be reduced to 20– due to suppression of GH production and/or GH or insu- 25 cm below the 50th percentile. While shorter stature lin-like growth hormone-I (IGF-I) resistance, as well as might help preserve muscle function, walking and stair climbing, it is a significant concern for most boys and their Management of short stature and growth failure in families. Increased weight for age is another concern, as DMD should be individualized to address the needs of well as the fact that the onset of puberty may be delayed each patient. Management options include: (1) no interven- by 3–5 years or more. Boys who are ambulating in their tion (standard of care and acceptable for many), (2) reduc- teens are frustrated because people often think they are tion of CS dose or intermittent regimens (not an option in much younger than they are. Their voice remains high most cases), or (3) GH (or IGF-I) therapy.
and they have little facial hair. Their small penis is often Dr. Rutter and the other participants debated the lack a concern voiced by parents, even if usually not by the boys of data regarding GH in DMD, and the conflicting opin- themselves. Their bone age can be delayed significantly (by ions about them . Although an isolated case report from 2–4 years). The impact of deflazacort compared to predni- the 1980s suggested that GH might be detrimental in sone on bone health is less well understood. Prolonged DMD, this hypothesis was not held up by subsequent stud- ambulation during CS treatment clearly benefits bone ies (including a randomized controlled study of 83 boys) health. To date, the incidence of long bone fractures has using a GH inhibitor which failed to show a benefit .
not increased significantly. This might change with longer A case report of GH treatment of a DMD boy with GH follow-up as the boys are ambulating 3–5 years longer deficiency showed improved growth velocity and motor and therefore at greater risk for fragility fractures from fall- function while a small, short-term study of GH in ing. The increased incidence of vertebral fragility fractures DMD and Becker MD suggested cardiovascular benefits in the CS-treated boys may not be explained by CS alone.
with improved systolic function Dr. Rutter reported Boys not treated with CS have reduced spinal BMD and her experience with GH in 39 DMD boys: during the first most have had spinal surgery to stabilize their spine. This year on therapy, there was improved linear growth and procedure might protect the vertebrae from fractures sec- body mass index (BMI), with no detrimental effects on neu- ondary to osteoporosis and mechanical stresses. Further romuscular and cardiopulmonary function Finally, studies are needed. Finally, it should be noted that the boys IGF-I (a hormone which mediates many of the actions of and their families want more effective strategies for the pre- GH) has been shown to improve muscle strength and sur- vention and treatment of the side-effects commonly associ- Dr. Rutter also discussed that chronic high-dose CS Dr. Alan Rogol reported the anabolic effects of growth therapy for DMD frequently results in absent, delayed or hormone (hGH) on striated muscle. In subjects with myo- arrested puberty. Typically, without CS therapy, boys with tonic muscular dystrophy and limb-girdle muscular dystro- DMD progress through puberty appropriately. However, phy, recombinant (r)hGH is anabolic with positive changes CS excess inhibits production of hypothalamic-pituitary in the balances of nitrogen, phosphorus, sodium, potas- hormones regulating puberty, resulting in testosterone Please cite this article in press as: Bianchi ML et al., Endocrine Aspects of Duchenne Muscular Dystrophy, Neuromuscul Disord (2011), doi: M.L. Bianchi et al. / Neuromuscular Disorders xxx (2011) xxx–xxx deficiency due to hypogonadotropic hypogonadism. Lack weight affects motor function and mobility, and limits the of puberty may have a significant negative impact on both caregivers’ ability to lift and transfer boys, affecting the body image and bone health, which are already adversely quality of life and functioning of the entire family.
affected by DMD itself and its treatment. Dr. Rutter In DMD the mainstays of prevention and treatment of reported that at the Neuromuscular Center at Cincinnati excessive weight gain involve addressing CS dose and for- Children’s Hospital, 44 DMD boys treated with long-term mulation and dietary control, due to the limited practical daily CS aged 13 years or greater (including 31 boys aged value of exercise recommendations. In individuals with sig- at least 14 years), were evaluated for puberty by measuring nificant insulin resistance, medications could be considered.
serum testosterone concentrations and/or a genital exami- CS are typically initiated using weight-based dosing at nation performed by a pediatric endocrinologist. All but supra-pharmacological doses (prednisone 0.75 mg/kg/day one boy were prepubertal, which underscores the potential or deflazacort 0.9 mg/kg/day). In some institutions, the doses may be periodically increased in line with weight Treatment comprises replacement therapy with testos- gain, aside from clinical response. In general, the smallest terone, starting with low doses by age 14 years, or perhaps dose to achieve a desired effect should be used, and caution earlier, approximating a more normal age of onset of pub- should be exercised before increasing doses based on erty. Doses are gradually increased over 3–4 years until adult replacement doses are attained. Low-dose testoster- Nutritional intake is a key component of management.
one replacement can be administered by monthly intramus- DMD boys require fewer calories compared to average cular injections or by daily transdermal application.
healthy children (ambulatory boys need about 80%, while In general, testosterone promotes virilization and non-ambulatory boys about 70%). It is important to indi- growth, with gains in bone density, muscle strength and vidualize recommendations based on physical ability and energy levels. However, promotion of growth in the setting ambulatory status. Nutritional counseling should ensue of CS-induced growth failure, and gains in muscle strength from the outset, well before CS are initiated. General prin- in the presence of a progressive myopathy may not be real- ciples which underlie a low glycemic index diet may help istic expectations for DMD boys. Adverse effects in this age with weight control and prevention of hyperinsulinemia.
group are infrequent and minor, including acne, oily skin These include avoidance of simple sugars, portion control, increased fiber and whole grains, and limited fat intake.
Management of puberty in DMD boys on CS presents Medications, such as metformin, could be considered in some additional pertinent issues which require consider- select cases in whom weight gain is severe and insulin resis- ation before embarking on therapy. Osteoporosis may tance or glucose intolerance are present. Metformin is an prompt the decision to initiate treatment due to beneficial insulin-sensitizing agent which is effective in type 2 diabetes effects for bone health. Conversely, in cases with extreme and insulin resistance, and may result in associated weight short stature, testosterone replacement will eventually loss. A case series of DMD boys on CS who had extreme bring about bone age advancement and epiphyseal fusion, weight gain and insulin resistance were treated with metfor- and final height will be further compromised. The decision min at Cincinnati Children’s Hospital Neuromuscular Cen- to undertake treatment should involve a frank discussion ter , and showed short term weight loss or slowing of of the pros and cons, and individualized according to the the rate of weight gain, with improvement in body mass boy’s concerns and wishes. Fundamentally, there needs to index. While this is an option which could be considered, be awareness by neurologists and timely referral to endo- currently there are insufficient data to recommend metfor- crinologists, so that this issue can be addressed. The evalu- min as standard of care for treatment or prevention of ation and management of puberty in DMD is complex, and should be addressed together with other endocrine issues.
Dr. Rutter emphasized that boys with DMD are at high Dr. Maria Luisa Bianchi emphasized that among the risk of excessive weight gain, insulin resistance and type 2 endocrine problems related to DMD, alterations of bone diabetes mellitus, due to chronic treatment with CS and metabolism, with a reduction of bone mineral content progressive muscle weakness. CS may stimulate appetite (BMC, also referred to as “bone mass”) and bone mineral and food intake, and act on metabolic pathways in liver density (BMD), are particularly relevant (see Note 1). For and fat cells to promote insulin resistance, hyperglycemia this reason, bone density measurement should be consid- and visceral adiposity. Progressive muscle weakness limits ered part of the normal clinical evaluation in these boys.
physical activity and results in eventual loss of independent It is necessary to remember that the evaluation of bone ambulation, exacerbating weight gain. Excessive weight mass and its change in growing subjects is very complex, gain negatively impacts DMD boys in many ways. It as the growth process implies rapid changes in bone size, may lead to carbohydrate intolerance and diabetes, and shape and mineral content. Considering these physiological be detrimental for pulmonary and cardiac function. Excess changes, that may be altered by the presence of pathological Please cite this article in press as: Bianchi ML et al., Endocrine Aspects of Duchenne Muscular Dystrophy, Neuromuscul Disord (2011), M.L. Bianchi et al. / Neuromuscular Disorders xxx (2011) xxx–xxx conditions, BMC and BMD are very difficult to evaluate in nous infusion of zoledronic acid (5 mg) once a year seemed effective for both the prevention and treatment of Dual X-ray absorptiometry (DXA) is the most widely used densitometric technique in children. A limitation of The fact that most data on BP use in children come from DXA is that it only calculates an “areal” BMD (the ratio the treatment of osteogenesis imperfecta, essentially with of BMC to the projection area of the scanned bones). This, intravenous pamidronate was discussed. One of the first for mathematical reasons, overestimates the true BMD studies with an oral BP in children was performed by Dr.
value (BMC/bone volume) for increasing bone volume, Bianchi: CS-treated children affected by juvenile rheuma- thus requiring appropriate corrections to evaluate the toid arthritis showed a significant increase in BMD and a actual BMD value in subjects with a small body size for reduction of fractures with alendronate treatment. Alendr- age, and the actual BMD changes during growth. To over- onate proved to be safe and had no negative effects on come this limitation, different correction methods have been proposed . Since boys affected by DMD (espe- Recently, the efficacy of intermittent (pulse) therapy cially receiving CS treatment) have a reduced growth, their with teriparatide (recombinant form of parathyroid hor- DXA values must always be adequately corrected in order mone) has been demonstrated in adult GIO Regarding disuse osteoporosis, its most common causes Lumbar spine and total body measurements are the are prolonged bed confinement, immobilization due to most widely used in children, and those with more pub- motor paralysis and fracture casts. Rehabilitation, includ- lished data. However, Dr. Bianchi reported a recent devel- ing bed positioning, therapeutic exercise and electrical opment of DXA, the scanning of lateral distal femur, that stimulation are the basic treatments to avoid disuse OP.
is quite promising for children with motor disabilities such Animal studies and double-blind studies on small as cerebral palsy and also for children with DMD with lim- groups of children with cerebral palsy demon- strated the efficacy of BPs in inhibiting bone resorption An important aspect of DXA is that it can be used to predict the risk of fractures before they occur. There is evi- Many studies have demonstrated the influence of phys- dence for a strong relationship between low BMD and frac- ical activity on bone during growth. Especially in prepuber- ture risk in adults, and some recent studies have also found tal children, exercise increases bone density and bone a similar relationship in children This aspect may strength . More recently it was demonstrated that be very relevant in DMD, in which the fracture rate seems low-magnitude mechanical stimuli are anabolic to bone to be increased, even if a precise estimate of the vertebral in young females with low bone density and increase BMD at the spine and lower limbs . Following this, The treatment options in glucocorticoid-induced osteo- there are ongoing trials in children with disabilities, includ- porosis (GIO) and disuse osteoporosis were also discussed, ing one by Dr. Bianchi in children with DMD using a Dr. Bianchi stressed that bone loss is 6–12% within the first year of CS treatment, and that the fracture risk increases rapidly in the first 3 months of treatment. Frac-tures may occur in up to 30–50% of adult subjects receiving Until recently, the physicians’ approach to the endocrine chronic CS therapy. Vertebral fractures are often asymp- complications of DMD was essentially inactive. Currently, tomatic, probably because of CS-induced analgesia. There some centers are in favor of a more reactive approach. But are only few epidemiological data about fractures in chil- on the basis of the latest clinical and research develop- dren treated with long-term CS No safe dose seems ments, it is probably time to be proactive, that is, to think to exist, since an increase in vertebral fractures has been about preventing the undesirable secondary manifestations observed with as little as 2.5 mg of prednisone daily. King of the disease before their appearance and to implement et al. observed that CS-treated boys with DMD have strategies to avoid or reduce the effects of these an increased risk of vertebral and lower limb fractures with respect to untreated DMD boys. Vertebral compression It must be noted that, until now, the endocrine problems fractures were observed in 32% of the CS-treated group, of DMD have not been explored in depth. At the Florence compared with none in the CS-naive group. Long bone 2009 meeting, there was a very lively debate, and even fractures were 2.6 times more frequent in CS-treated though no definitive conclusions could be reached, the experts agreed on some starting key-points.
Bisphosphonates (BPs) are the current standard of care for the prevention and treatment of GIO. Alendronate and 1. Regarding height, there is evidence that DMD does risedronate were the first BPs used in GIO and their effi- influence height and that short stature is not detrimental cacy was demonstrated in both female and male patients to function. In addition, chronic CS treatment may over a wide age range (17–85 years) . In a recent dou- cause growth failure. However, data on height are not ble-blind study on adults with GIO , a single intrave- regularly collected in DMD patients, and this must be Please cite this article in press as: Bianchi ML et al., Endocrine Aspects of Duchenne Muscular Dystrophy, Neuromuscul Disord (2011), doi: M.L. Bianchi et al. / Neuromuscular Disorders xxx (2011) xxx–xxx changed. It is also important to remember that linear regimen of CS administration may have important height measurement is not trivial in children with diffi- effects on bone, and this aspect will be addressed in a culty to stand-up normally. Thus, it is necessary to stan- forthcoming international study (“Duchenne muscular dardize the methods for measuring height in boys with dystrophy: double-blind randomized trial to find opti- DMD and to widely disseminate these standards to mum steroid regimen (FOR-DMD)” – Study Chair: obtain comparable data. National specific growth charts Kate Bushby and Robert C. Griggs).In the presence of should be used to evaluate height deficits.In the presence vertebral fractures and reduced BMD, BPs should be of reduced height, serum GH screening indices should considered as a treatment option, with due caution for be evaluated, with consideration given to more detailed children. However, there are no large randomized dou- GH testing if indicated. If GH treatment is decided, tim- ble-blind studies to support decisions about the drug, ing and therapeutic goals should be individualized, and the administration route, the dose and the duration of therapy should be carefully monitored, considering the difficulties of accurate height measurement in boys withDMD, and the fact that there are inadequate data In conclusion, we must be fully aware that we are mov- regarding benefit or harm of rhGH in the DMD-affected ing within an unexplored area. This article is only a preli- minary contribution, and a partial response to the “cry 2. Pubertal delay or complete suppression of puberty may for help” coming from the patients and their families, accompany prolonged CS use in DMD, as in many who would like to see a more rapid progress than is nor- other chronic diseases. Testosterone replacement is pos- mally achieved by evidence-based medicine.
sible, and preliminary experience (see above) has been Considering the difficult problems that the “older” sub- positive.Like growth, pubertal stage must also be regu- jects with DMD are currently posing and would like to see larly assessed. The choice to treat and the timing of resolved (fewer side effects of CS therapy, improved interventions must take into account the individual’s self-esteem and quality of life), more active collaboration specific needs.Presently, there are no data on the psycho- between different specialists and different centers is logical impact of reduced height and pubertal delay. All these aspects become relevant for boys with DMD espe- Large, longitudinal, controlled studies are urgently cially during adolescence and in young adulthood when needed to give scientifically valid answers to the many open socialization and comparison with same-age subjects are common. The requests of being “like the others” mustbe taken into account, and the risks and benefits ofinterventions (including psychological well-being) must 3. Excessive weight gain is very frequent in boys with Maria Luisa Bianchi, Istituto Auxologico Italiano DMD due to chronic treatment with CS and also to reduced mobility. Dietary evaluation by skilled dieti- Brian Denger, Parent Project Muscular Dystrophy, cians should be part of the routine evaluation. Glucose metabolism should be evaluated: paired glucose and Douglas Biggar, Holland Bloorview Kids Rehabilitation insulin levels, with glycosylated hemoglobin levels, and oral glucose tolerance testing (OGTT) could be consid- Filippo Buccella, Parent Project Muscular Dystrophy, ered in the presence of excessive weight gain, increased laboratory values (serum glucose, insulin or glycosylated Katherine Bushby, International Centre for Life, New- hemoglobin).The experts agreed on the relevance of diet and careful weight monitoring. Some experts suggested Chris Condin, University of British Columbia, Vancou- that, in DMD boys, caloric intake should be about 80% of normal intake for ambulant boys, and 70% for Diana Escolar, Kennedy Kreiger Institute, Baltimore, non-ambulant boys.Some preliminary data suggest that metformin may be useful in patients with proven insulin Kevin Flanigan, University of Utah, Salt Lake City, 4. Regarding bone health, the relationship between BMC/ Patricia Furlong, Parent Project Muscular Dystrophy, BMD and future fracture risk in children/adolescents underscores that bone mass evaluation should become Peter C. Hindmarsh, University College, London, UK.
a standard in the follow-up of children with DMD.Gen- Sally Hoffmeister, Parent Project Muscular Dystrophy, eral measures to optimize bone mass gain should be started as soon as possible. They include individualized Tony Huynh, Mater Children’s Hospital, South Bris- physical exercises, appropriate calcium and protein intake, supplementation of vitamin D (if needed, after Larry W. Markham, Cincinnati Children’s Hospital measuring 25-hydroxyvitamin D levels).The dose and Please cite this article in press as: Bianchi ML et al., Endocrine Aspects of Duchenne Muscular Dystrophy, Neuromuscul Disord (2011), M.L. Bianchi et al. / Neuromuscular Disorders xxx (2011) xxx–xxx Alan D. Rogol, University of Virginia, Charlottesville, [13] Gregorevic P, Plant DR, Lynch GS. Administration of insulin-like growth factor-I improves fatigue resistance of skeletal muscles fromdystrophic mdx mice. Muscle Nerve 2004;30:295–304.
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