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Commentary and Perspective   |    
Corticosteroids Can Reduce the Severity of Scoliosis in Duchenne Muscular DystrophyCommentary on an article by David E. Lebel, MD, PhD, et al.: “Glucocorticoid Treatment for the Prevention of Scoliosis in Children with Duchenne Muscular Dystrophy: Long-Term Follow-up”
Anne M. Connolly, MD1; Han Jo Kim, MD2; Keith H. Bridwell, MD3
1 Department of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri
2 Hospital for Special Surgery, Spine and Scoliosis Service, New York, NY
3 Washington University Orthopedics, St. Louis, Missouri
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None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.


Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Jun 19;95(12):e86 1-2. doi: 10.2106/JBJS.M.00428
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From the first work by Drachman et al. that recognized a benefit from corticosteroids1 in boys with Duchenne muscular dystrophy through the excellent randomized controlled trials (RCTs)2-5 of the 1980s and 1990s, the recognition that daily corticosteroids benefit boys with Duchenne muscular dystrophy is clear. More than forty years of work with hundreds of boys have demonstrated that corticosteroids prolong walking and improve the strength of boys with Duchenne muscular dystrophy. Deflazacort, available in Canada and Europe, is not approved by the U.S. Food and Drug Administration (FDA) for use in the United States. However, there are extensive long-term positive data showing that it is effective in boys with Duchenne muscular dystrophy6,7. Although weight gain with deflazacort is less than that with daily prednisone, other side effects, including loss of height, loss of bone density, and cataracts, do occur. The study by Lebel et al. clearly adds to these data with, to our knowledge, the longest continual follow-up of a treated cohort. However, the known side effects have led to many alternative regimens and drug formulations. Intermittent corticosteroid dosing regimens, including the twice-weekly or alternate-day regimens, show promise in minimizing side effects8-10, but long-term follow-up is not yet available.
Despite this extensive body of evidence, many boys with Duchenne muscular dystrophy are never offered corticosteroids because of known side effects. To try to address this discrepancy of care, a practice parameter was published by the American Academy of Neurology in 200511. Diagnostic management recommendations were agreed upon in an effort funded by the Centers for Disease Control and Prevention (CDC) to improve care12.
The present work by Lebel et al. clearly demonstrates that daily deflazacort prolongs life, delays deterioration in pulmonary function, and decreases the need for scoliosis surgery. This is a follow-up study of fifty-four boys who had been diagnosed with Duchenne muscular dystrophy. While still walking, they were enrolled in a nonrandomized comparative study of the glucocorticoid deflazacort. Thirty boys (56%) received glucocorticoid treatment, a decision made by their families and physicians. In this study, Lebel et al. defined scoliosis as a Cobb angle measurement of >20° on posteroanterior radiographs. Six (20%) of thirty boys in the glucocorticoid treatment group and twenty-two (92%) of twenty-four boys in the non-treatment group developed scoliosis and underwent spinal surgery. Some of the same authors from the study by Lebel et al. also recently published a study of a similar experience in which boys with Duchenne muscular dystrophy who had a daily dose of 0.9 mg per kilogram had a rate of scoliosis (also defined as >20°) of 27% (ten of thirty-seven)13. In both reports, the positive effect of corticosteroid treatment is clear.
All daily corticosteroids, either in the form of deflazacort or prednisone, have long-term consequences. The major side effect was cataracts, which developed in 70% of the treatment group, but required surgical treatment in only two of those twenty-one boys. Finally, the loss of linear growth was apparent as the treatment group measured 17 cm shorter with regard to mean height. The treatment group also had a higher mean weight compared with the non-treatment group.
The severe side effects related to corticosteroid use may be minimized by differing dosing regimens. Yilmaz et al.10 demonstrated similarly striking results in their cohort of eighty-eight patients. Of these, sixty-six patients who were on an alternate-day corticosteroid treatment did not develop scoliosis, whereas seven of the twenty-two in the control group developed scoliosis at a mean follow-up duration of 2.75 years. Ultimately, the optimal dosing regimen that maximizes the benefits and minimizes the side effects of corticosteroids needs to be determined to promote its more widespread use.
Ideally, an RCT is the gold standard for proving efficacy of a medical intervention. The large effect size noted in multiple reports on the effect of corticosteroids on scoliosis means that powering a study with the appropriate sample size to answer this question would not be overly ambitious10,14. However, the compelling benefits in this study and others would suggest that RCTs should be used only to determine the appropriate dosage regimen, not to answer a treat or not-to-treat question.
This excellent study offers long-term prospective data that physicians can use to encourage more families and their physicians to try corticosteroids in patients with Duchenne muscular dystrophy. The recommendations by the collaborative group also allow practical advice for adjusting dosing and ensuring that 100% of boys at least try corticosteroids in some form12.
Drachman  DB;  Toyka  KV;  Myer  E. Prednisone in Duchenne muscular dystrophy. Lancet.  1974 Dec 14;2(  7894):1409-12.[CrossRef]
 
Brooke  MH;  Fenichel  GM;  Griggs  RC;  Mendell  JR;  Moxley  R;  Miller  JP;  Province  MA. Clinical investigation in Duchenne dystrophy: 2. Determination of the “power” of therapeutic trials based on the natural history. Muscle Nerve.  1983 Feb;6(  2):91-103.[CrossRef]
 
Brooke  MH;  Fenichel  GM;  Griggs  RC;  Mendell  JR;  Moxley  RT  3rd;  Miller  JP;  Kaiser  KK;  Florence  JM;  Pandya  S;  Signore  L;  King  W;  Robison  J;  Head  RA;  Province  MA;  Seyfried  W;  Mandel  S. Clinical investigation of Duchenne muscular dystrophy. Interesting results in a trial of prednisone. Arch Neurol.  1987 Aug;44(  8):812-7.[CrossRef]
 
Brooke  MH;  Griggs  RC;  Mendell  JR;  Fenichel  GM;  Shumate  JB;  Pellegrino  RJ. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve.  1981 May-Jun;4(  3):186-97.[CrossRef]
 
Griggs  RC;  Moxley  RT  3rd;  Mendell  JR;  Fenichel  GM;  Brooke  MH;  Pestronk  A;  Miller  JP;  Cwik  VA;  Pandya  S;  Robison  J;  King  W;  Signore  L;  Schierbecker  J;  Florence  J;  Matheson-Burden  N;  Wilson  B. Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months). Neurology.  1993 Mar;43(  3 Pt 1):520-7.[CrossRef]
 
Biggar  WD;  Harris  VA;  Eliasoph  L;  Alman  B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord.  2006 Apr;16(  4):249-55.  Epub 2006 Mar 20.[CrossRef]
 
Biggar  WD;  Politano  L;  Harris  VA;  Passamano  L;  Vajsar  J;  Alman  B;  Palladino  A;  Comi  LI;  Nigro  G. Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols. Neuromuscul Disord.  2004 Sep;14(  8-9):476-82.[CrossRef]
 
Connolly  AM;  Schierbecker  J;  Renna  R;  Florence  J. High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy. Neuromuscul Disord.  2002 Dec;12(  10):917-25.[CrossRef]
 
Escolar  DM;  Hache  LP;  Clemens  PR;  Cnaan  A;  McDonald  CM;  Viswanathan  V;  Kornberg  AJ;  Bertorini  TE;  Nevo  Y;  Lotze  T;  Pestronk  A;  Ryan  MM;  Monasterio  E;  Day  JW;  Zimmerman  A;  Arrieta  A;  Henricson  E;  Mayhew  J;  Florence  J;  Hu  F;  Connolly  AM. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology.  2011 Aug 2;77(  5):444-52.  Epub 2011 Jul 13.[CrossRef]
 
Yilmaz  O;  Karaduman  A;  Topaloğlu  H. Prednisolone therapy in Duchenne muscular dystrophy prolongs ambulation and prevents scoliosis. Eur J Neurol.  2004 Aug;11(  8):541-4.[CrossRef]
 
Moxley  RT  3rd;  Ashwal  S;  Pandya  S;  Connolly  A;  Florence  J;  Mathews  K;  Baumbach  L;  McDonald  C;  Sussman  M;  Wade  C; Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology.  2005 Jan 11;64(  1):13-20.[CrossRef]
 
Bushby  K;  Finkel  R;  Birnkrant  DJ;  Case  LE;  Clemens  PR;  Cripe  L;  Kaul  A;  Kinnett  K;  McDonald  C;  Pandya  S;  Poysky  J;  Shapiro  F;  Tomezsko  J;  Constantin  C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol.  2010 Feb;9(  2):177-89.  Epub 2009 Nov 27.[CrossRef]
 
McAdam  LC;  Mayo  AL;  Alman  BA;  Biggar  WD. The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol.  2012 May;31(  1):16-20.
 
Alman  BA;  Raza  SN;  Biggar  WD. Steroid treatment and the development of scoliosis in males with Duchenne muscular dystrophy. J Bone Joint Surg Am.  2004 Mar;86(  3):519-24.
 

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References

Drachman  DB;  Toyka  KV;  Myer  E. Prednisone in Duchenne muscular dystrophy. Lancet.  1974 Dec 14;2(  7894):1409-12.[CrossRef]
 
Brooke  MH;  Fenichel  GM;  Griggs  RC;  Mendell  JR;  Moxley  R;  Miller  JP;  Province  MA. Clinical investigation in Duchenne dystrophy: 2. Determination of the “power” of therapeutic trials based on the natural history. Muscle Nerve.  1983 Feb;6(  2):91-103.[CrossRef]
 
Brooke  MH;  Fenichel  GM;  Griggs  RC;  Mendell  JR;  Moxley  RT  3rd;  Miller  JP;  Kaiser  KK;  Florence  JM;  Pandya  S;  Signore  L;  King  W;  Robison  J;  Head  RA;  Province  MA;  Seyfried  W;  Mandel  S. Clinical investigation of Duchenne muscular dystrophy. Interesting results in a trial of prednisone. Arch Neurol.  1987 Aug;44(  8):812-7.[CrossRef]
 
Brooke  MH;  Griggs  RC;  Mendell  JR;  Fenichel  GM;  Shumate  JB;  Pellegrino  RJ. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve.  1981 May-Jun;4(  3):186-97.[CrossRef]
 
Griggs  RC;  Moxley  RT  3rd;  Mendell  JR;  Fenichel  GM;  Brooke  MH;  Pestronk  A;  Miller  JP;  Cwik  VA;  Pandya  S;  Robison  J;  King  W;  Signore  L;  Schierbecker  J;  Florence  J;  Matheson-Burden  N;  Wilson  B. Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months). Neurology.  1993 Mar;43(  3 Pt 1):520-7.[CrossRef]
 
Biggar  WD;  Harris  VA;  Eliasoph  L;  Alman  B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord.  2006 Apr;16(  4):249-55.  Epub 2006 Mar 20.[CrossRef]
 
Biggar  WD;  Politano  L;  Harris  VA;  Passamano  L;  Vajsar  J;  Alman  B;  Palladino  A;  Comi  LI;  Nigro  G. Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols. Neuromuscul Disord.  2004 Sep;14(  8-9):476-82.[CrossRef]
 
Connolly  AM;  Schierbecker  J;  Renna  R;  Florence  J. High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy. Neuromuscul Disord.  2002 Dec;12(  10):917-25.[CrossRef]
 
Escolar  DM;  Hache  LP;  Clemens  PR;  Cnaan  A;  McDonald  CM;  Viswanathan  V;  Kornberg  AJ;  Bertorini  TE;  Nevo  Y;  Lotze  T;  Pestronk  A;  Ryan  MM;  Monasterio  E;  Day  JW;  Zimmerman  A;  Arrieta  A;  Henricson  E;  Mayhew  J;  Florence  J;  Hu  F;  Connolly  AM. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology.  2011 Aug 2;77(  5):444-52.  Epub 2011 Jul 13.[CrossRef]
 
Yilmaz  O;  Karaduman  A;  Topaloğlu  H. Prednisolone therapy in Duchenne muscular dystrophy prolongs ambulation and prevents scoliosis. Eur J Neurol.  2004 Aug;11(  8):541-4.[CrossRef]
 
Moxley  RT  3rd;  Ashwal  S;  Pandya  S;  Connolly  A;  Florence  J;  Mathews  K;  Baumbach  L;  McDonald  C;  Sussman  M;  Wade  C; Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology.  2005 Jan 11;64(  1):13-20.[CrossRef]
 
Bushby  K;  Finkel  R;  Birnkrant  DJ;  Case  LE;  Clemens  PR;  Cripe  L;  Kaul  A;  Kinnett  K;  McDonald  C;  Pandya  S;  Poysky  J;  Shapiro  F;  Tomezsko  J;  Constantin  C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol.  2010 Feb;9(  2):177-89.  Epub 2009 Nov 27.[CrossRef]
 
McAdam  LC;  Mayo  AL;  Alman  BA;  Biggar  WD. The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol.  2012 May;31(  1):16-20.
 
Alman  BA;  Raza  SN;  Biggar  WD. Steroid treatment and the development of scoliosis in males with Duchenne muscular dystrophy. J Bone Joint Surg Am.  2004 Mar;86(  3):519-24.
 
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