making muscle wasting history

Bone Health in Duchenne Muscular Dystrophy
A WORKSHOP REPORT FROM THE MEETING IN CINCINNATI, OHIO, JULY 8, 2004
Biggar WD1 Bachrach LR2 Henderson RC3 Kalkwarf H4 Plotkin H5 Wong BL4

Bloorview MacMillan Children’s Centre
University of Toronto, Toronto, ON, Canada
Stanford Medical Center
Stanford, CA, USA
University of North Carolina
Chapel Hill, NC, USA
Cincinnati Children' Hospital Medical Centre
Cincinnati, OH, USA
College of Medicine UNMC
Omaha, NE, USA

INTRODUCTION

Duchenne muscular dystrophy is the most frequently occurring of the childhood muscular dystrophies and is inherited as an X-linked recessive disorder (1-3). Bone health is frequently compromised and fractures are more common in this patient population (4-11). Fractures impact negatively on their quality of life and may contribute to the loss of ambulation (4,5).

The goals of this workshop were to:

1) review bone health in paediatrics,
2)review methods to evaluate bone health,
3)review the risk and consequences of a fracture in boys with DMD,
4)review non-pharmacologic and pharmacologic interventions to promote their bone health, and
5)identify the important “next steps” inorder to improve our understanding and management of the skeletal component of this multisystem and life-threatening disease.

Bone Health in Paediatrics

Bone strength is determined by its mass, size, geometry and quality. Fragility fractures occur when bone strength is markedly reduced.

A fragility fracture is one that occurs with minimal trauma, e.g. falling from a standing height, or less, or following no apparent of trauma. The diagnosis of osteoporosis can be made when an individual sustains a fragility fracture. The clinician is interested in identifying those with diminished bone strength before a fracture occurs. In adults, osteoporosis can be diagnosed by detecting low bone density since this measurement is a good predictor of future fracture in the elderly.

The bulk of peak bone mass is achieved during the third decade (12). Failure to achieve an optimum peak bone mass increases the risk of fracture throughout the reminder of adulthood (12). Bone mineral accrual is an individual and very dynamic process. As bones grow, they change in size and shape. The size and shape of bones is important for bone strength. A 10% increase in the radius of a bone can increase the strength by as much as 70% (13, 14). The acquisition of bone mineral is completed first in the axial skeleton (spine and hip regions) first followed by the appendicular skeleton (arms and legs).

Determinants of bone strength

Hereditary accounts for 60 – 80% of the differences in between individuals! Of the modifiable factors that can influence bone strength, mobility is likely the most important. The greater the amount of loading or strain on the skeleton, the greater the influence on bone mass and geometry. For example, walking has less impact on bone density than running, and running has less impact than gymnastics. Bones most affected are those “loaded” sites for example, femur, tibia and fibula compared to humerus, radius and ulna. The effects of physical activity are enhanced by adequate dietary calcium (15). Activity early in life can make bones bigger and stronger. By contrast, even short periods of weightlessness during space travel or bedrest leads to bone loss.

Puberty is a critical time for healthy bone production. The sex steroids increase the amount of bone mineral laid down and the size and shape of growing bones. Delayed puberty or permanent hypogonadism may result in reduced peak bone mass.

The effects of activity on the adolescent skeleton are modified by estrogen and testosterone as well. Depending upon gender, pubertal stage, and the type of activity, exercise can increase the amount of bone mineral laid down on the inner aspect of bone (endocortical apposition) or may increase bone size by stimulating the addition of bone mineral to the outer aspect of bone (periosteal expansion). Cortical thickness may increase as well (16).Important questions about the impact of physical activity remain. For example, do gender and ethnicity have a role; is there a “critical period” to optimize the impact of physical activity and how long do the benefits of physical activity on bone last?

Calcium

Calcium is important for bone mineralization. The recommended intake of calcium (mg/day) is 400-600 mg. in young children (1 – 5 years), 800 – 1,200 mg. for older children (8 – 10 years) and 1200 – 1500 mg. for adolescents and young adults (11 – 24 years) (17). The best source of calcium is a healthy balanced diet. There is concern that calcium intake falls short during the teen years at a time when needs are greater and the foundations for healthy bones are being laid. This is larglely due to reduced intake of dairy products, resulting from a preference for soft drinks, lactose intolerance and ethnic preferences. Dairy products provide 75% of dietary calcium.

Vitamin D

Vitamin D is important for skeletal health because it aids in calcium absorption. Deficiency of vitamin D is increasing with the decline in dairy consumption since milk is one of the few vitamin D fortified foods. Vitamin D can also be synthesized in the skin with exposure to natural sunlight. Vitamin D synthesis is hampered by avoidance of sun exposure and the increased use of sunscreens. The combination of reduced intake of calcium and hypovitaminosis D may compromise optimum bone health.

Similar to other conditions of reduced mobility, low bone mass is frequently observed in boys with DMD. The bones become thin and under demineralized. The appearance of ossification centres maybe delayed (7). Even while boys with DMD remain ambulatory, bone mineral density of the proximal femur may be diminished (5, 18). With loss of ambulation, bone mineral density decreases dramatically (5,15). As a result, the risk of fractures of the long bones is increased to approximately 20%, but may be as high as 44% (5). Vertebral fractures are not common.

In the absence of a cure for DMD, corticosteroids offer the only treatment proven to preserve muscle function (19 -21). Their mechanism(s) of action remains unclear. Prednisone has been documented to delay the loss of muscle function but is associated with significant side effects (22-26). Deflazacort, an oxazolone derivative of prednisolone, also has long-term benefits for preserving skeletal muscle (27 – 29), cardiac (30) and pulmonary function (29 – 31), and delaying the need for scoliosis surgery (32), but with fewer side effects than prednisone, particularly weight gain (19, 33-35). Asymptomatic cataracts that do not require treatment are reported in 30% of boys treated with long-term deflazacort (29). There is a general consensus that the most effective dose of corticosteroid is prednisone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day (21). Despite the benefits of corticosteroids, there is a concern that the long-term use of either drug (prednisone or deflazacort) may exacerbate the already-compromised skeleton of boys with DMD. Corticosteroids reduce the action of vitamin D on the intestine and increase calcium excretion in the urine Gonadotropin release from the pituitary is reduced, leading to lower levels of estrogen and androgen needed for bone health. Bone resorption is increased while bone formation is reduced. The use of corticosteroids in DMD may compromise bone health but in early reports, it does not appear to greatly increase the risk of fractures in long bones (6,8). However, vertebral fractures, uncommon in DMD, may be more frequent in boys treated with corticosteroids (36-38). Fortunately, these compression fractures are not usually painful and most frequently, they are identified as incidental findings on routine spine X-rays.

In summary, there are many threats to bone health in DMD, including the reduced mobility and the associated reduction of biomechanical activity of muscle on bone. Corticosteroids may further compromise bone health. The impact of genetics on bone health and the mediators of inflammation generated from the dystrophin deficient muscle are unknown.

Methods to Evaluate Bone Health

A history of previous fracture, particularly a fragility fracture, or a history of multiple fractures suggests compromised bone health. There are several laboratory investigations, both non-invasive and invasive, to study bone health.

Non-invasive indicators of bone health

Non-invasive investigations include bone densitometry and measuring markers of bone turnover in blood and urine.While plain X-rays might suggest reduced bone density, a 30 – 40% reduction in bone mineral density must occur before a visible change on an X-ray is evident. Plain X-rays are not quantitative and are not helpful for measurement of bone mineral density. Dual energy X-ray absorptiometry (DXA) is the method of choice for measuring bone mineral density (39). It involves a low dose of radiation. It is readily available and good paediatric/normative data are established.

It is precise and easily reproducible. It takes a few minutes to perform and most children tolerate the procedure easily. Sedation is not required. However, DXA has some limitations. Small bones, joint contractures and spinal hardware are problematic for reliable testing. DXA does not differentiate trabecular bone from cortical bone. It measures areal bone mineral density not volumetric bone. DXA scans calculate total body, hip and spine mineral density. In adults, bone mineral density is expressed as a T-score which represents the number of standard deviations that bone mass varies from the mean for healthy young adults. T-scores are not appropriate for use until age 20, since younger patients will not yet have achieved adult bone mass. Bone density results in younger children should be compared with age and gender matched controls, generating a Z-score. Interpretation of DXA results in pediatric patients is very challenging. Boys with DMD often have delayed growth and puberty as well as diminished muscle mass. With corticosteroids, these changes may be even greater. Bone size, maturity, and body composition each affect the DXA reading and the influence of these variables must be considered.

While T-scores in elderly adults provide a reasonable estimate of fracture risk, the risk of fractures in children based upon Z-scores is not established. For this reason, the diagnosis of osteoporosis in pediatrics and decisions about treatment options (e.g. withholding or reducing the dosage of steroids or initiating bisphosphonates) cannot be based on BMD alone in pediatric patients. Peripheral quantitative computed tomography (PQCT) is primarily a research tool to measure volumetric bone mineral density (40). It can distinguish trabecular from cortical bone. The usual sites to measure trabecular and cortical bone are the radius and tibia. Thin, cross-sectional slices of bone are measured. It is difficult to study children under 8 years of age without sedation. For longitudinal studies, it is difficult to precisely locate the place where the previous PQCT was estimated. Reference normative data are being developed. In the future, PQCT may offer important alternatives to DXA in studying bone health but at present, it remains primarily an important research tool.

The other non-invasive test of bone health is bone markers. Bone markers, as a reflection of bone turnover, can be assayed in blood and urine. The biochemical assays include serum osteocalcin, procollagen and collagen markers, calcium and vitamin D, bone specific alkaline phosphatase, urine deoxypyridinoline (D-Pyr), pyridinoline (Pyr), and hydroxyproline. Tests of bone turnover are very challenging to interpret in children and are not yet ready or appropriate for clinical practice (41).

Invasive indictors of bone health

The bone biopsy provides additional material for a more precise histologic estimate of bone health. It is invasive and usually requires the children to be sedated. It is not generally available for routine clinical use.

Interventions to promote Bone Health

Two approaches, pharmacologic and non-pharmacologic are available. The central pillar to non-pharmacologic promotion of healthy bones is a balanced diet. The best source of calcium is dietary. Daily calcium requirements for children and adolescents are established (17). Sunshine is a good source of vitamin D. The use of sunscreens and reduced outdoor activities may contribute to hypovitaminosis D. The adequacy of vitamin D stores can be checked by measuring serum 25 hydroxyvitamin concentrations, with the goal being a level> 20 ng/ml. The serum concentration is usually lowest during the winter months when the exposure to sunshine is less than during the summer months. When in doubt, supplementing with vitamin D alone or in a multivitamin is reasonable. While adequate intake of calcium and vitamin D contribute to bone health and bone mineral density, there is no evidence that they are sufficient to reduce low impact fractures in patients on glucocorticoids (42).

Exercise, particularly high-impact activities, improves bone mineral density. For less mobile children, any weight bearing with or without the aid of long-leg braces and standing frames for example, may help prevent bone loss. Similarly, standing on a platform generating low-magnitude, high-frequency mechanical stimuli may improve tibial bone mineral density (43). These observations may be relevant for treatment strategies in boys with DMD and reduced mobility.

Pharmacologic interventions for treating reduced bone mineral density are well established in adults. Bisphosphonates are the most widely used drugs to treat osteoporosis because these agents reduce bone resorption (44). There are several preparations that vary in their potency and route of administration. In general, they target the number and activity of bone-resorbing osteoclasts. In adults, prevention and treatment of osteoporosis includes calcium, vitamin D and bisphosphonates. In adults, the bisphosphonate “alendronate” has been shown to be safe and efficacious in the treatment of steroid-induced bone loss and reduce the risk of fracture.

In children, general measures such as optimizing nutrition and maximizing physical activity are used to foster bone health. None of the drugs used to treat osteoporosis in adults has yet been established as safe and effective in randomized controlled trails in pediatrics. However, preliminary observational data suggest that bisphosphonates may be useful in children with low bone mass. Bisphosphonates have been used to treat reduced bone mineral density in boys with DMD and other clinical conditions (45 – 53). Intravenous bisphosphonates, such as pamidronate, have been used more often in children than oral bisphosphonates. However, an oral bisphosphonate is less costly, simpler to administer, and thus if tolerated, might be preferable to Intravenous therapy. Oral bisphosphonates have seen limited use in children, some of whom have been taking corticosteroids. When taken properly, oral alendronate is associated with few side effects and minimal gastrointestinal upset and improves bone mineral density in boys with DMD treated with deflazacort (51) as determined by DXA. However, to date, there is no evidence that long-term treatment with bisphosphonates reduces the morbidity or the risk of low impact fractures in boys with DMD whether or not they are treated with corticosteroids.

Summary and next steps

From the work shop discussions, there is general agreement that:
1) DMD is associated with reduced mobility.
2) Boys with DMD have an increased risk of fractures, particularly long bones.
3) DMD patients have reduced bone mineral density.
Corticosteroids may be associated with a further reduction in bone mineral density.
4) The bone mineral density Z-score cannot be used to predict fracture risk, and it should not be used alone to make treatment decisions.
5) Corticosteroids may increase the risk of a vertebral compression fracture, many of which are asymptomatic.
Vitamin D and calcium contribute to bone health but have not been proven to reduce the risk of low-impact fractures.
6) The best sources of calcium and vitamin D are a balanced diet and sunshine.
7) It is recommended that boys with DMD have a serum vitamin D determined annually; supplementation is appropriate if the concentration is <20 ng/ml.

But, we need to determine:
1) How the best to assess and monitor bone health.
2) The natural history of bone health in DMD.
3) Risk factors that predict the likelihood of a low-impact fracture.
4)The contribution of Vitamin D and calcium to bone health in DMD.
5)Potential interventions involving weight-bearing activities to maintain bone strength.
6)What strategies are effective in preventing and treating reduced bone mineral density.
7)How to develop multicenter, collaborative study groups in order to.
8) Collect standardized, clinical and laboratory data on boys with DMD, and to collect clinical trials to improve bone health and quality of life for boys with DMD.

REFERENCES Dubowitz V. Muscle disorders in childhood, 2nd ed. London: WB Saunders,1995:34-133.

Hoffman EP. The muscular dystrophies. In: Rosenberg RN, ed. The molecular and genetic basis of neurologic disease, 2nd ed. Boston. Butterworth Heinemann, 1997:877-912.

McDonald CM. Abresch RT. Carter GT. Fowler WM. Johnson ER. Kilmer DD and Sigford BJ. Profiles of Neuromuscular Diseases: Duchenne Muscular Dystrophy. American Journal Physical Medicine and Rehabilitation 1995: 74(suppl), No. 5.:S50-S92.
Vestergaard P. Glerup H. Steffenson BF. Rejnmark L. Rahbeck J. Moseklide L. Fracture risk in patients with Duchenne muscular dystrophy and spinal muscular atrophy. J Rehab Med 2001:33 (4):150- 155.

Larson CM. Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. J Pediatr Orthop 2000:20:71-74.

McDonald DG. Kinali M. Gallagher AC. Mercuri E. Muntoni F. Roper H. Jardine P. Jones DH. Pike MG. Fracture prevalence in Duchenne muscular dystrophy. Dev Med Child Neurol 2002:44(10):695-698.

Hsu JD. Skeletal changes in children with neuromuscular disorders. In: Dixon AD. Sarnat BG. eds. Factors and mechanisms influencing bone growth. New York: Alan Liss, 1982:553-557.

Biggar WD. Politano L. Harris V. Passamano L. Vajsar J. Alman B. Pallidina A. DeLuca F. Nigro G. A report of two deflazacort treatment protocols in Duchenne muscular dystrophy. Neuromuscular Disorders 2003:13:630.

Bianchi ML. Cmiaz R. Badare M. et al. Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children. Arthritis Rheum 2000:43:1960-1966.

Siegel IM. Fractures of long bones in Duchenne muscular dystrophy. J Trauma 1977:17(3):219-222.

Hatano E. Masuda K. and Kameo H. Fractures in Duchenne Muscular Dystrophy – chiefly about their causes. J of Medical Sciences, Hiroshima 1986:(35), No.4, 429-433.

Boot AM. Engels MA. Boerma GJ. Krenning EP. De Muinck Keizer-Schrama SM. Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin endocrinol Metab 1997:82(8):2423-2428.

Bouxsein ML. Bone quality: where do we go from here? Osteoporosis Int 2003:5:118-127.

Orwell ES. Toward an expanded understanding of the role of the periosteum in skeletal health. J Bone Miner Res 2003:18(6):949-954.

Iuliano-Burns S. Saxon L. Naughton G. Gibbons K. Bass SL. Regional specificity of exercise and calcium during skeletal growth in girls: a randomized controlled trial. J Bone Miner Res 2003:18(1):156-162.

Kontulainen S. Sievanen H. Kannus P. Pasanen M. Vuori I. Effect of long-term impact-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: a peripheral quantitative computed tomography study between young and old starters and controls. J Bone Miner Res 2002:17(12):2281-2289.

Optimal calcium intake, Sponsored by National Institutes of Health Continuing Medical Education. 1995:11(5):409-417.
Aparicio LF. Jurkovic M. DeLullo J. Decreased bone density in ambulatory patients with Duchenne muscular dystrophy. J Pediatr Orthop 2002:22:179-181.

Manzur A. Kuntzer T. Pike M. Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2004:2:CD00372.

Wong BL. Christopher C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J Child Neurology 2002:17:183-190.

Naarden Workshop Reports, Treatment of Duchenne muscular dystrophy – defining the gold standards of management. 124th ENMC International Workshop:2004, Naarden, The Netherlands.
Dubowitz V. 75th ENMC International workshop: Treatment of muscular dystrophy. Neuromusc Disord 2000:10:313- 320.

Mendell JR. Moxley RT. Griggs RC. Brooke MH. Fenichel GM. Miller JP. King W. Signore L. Pandya S. Florence J. Randomized controlled trial of prednisolone in Duchenne’s muscular dystrophy. N.Engl J Med 1989: 321:1481-1482.

Griggs RC. Moxley RT. Mendell JR. Fenichel GM. Brooke MH. Pestronk A. Miller JP. Prednisolone in Duchenne dystrophy: a randomised trial defining the time course and dose response. Arch Neurol 1991:48:383- 388.

Angenlini C. Pegoraro E. Turella E. Intino MT. Pini A. Costa C. Deflazacort in Duchenne dystrophy: Study of long-term effect. Muscle Nerve,1994:17:386-391.

Rahman MM. Hannan MM. Mondol BA. Bhoumick NB. Haque A. Prednisolone in Duchenne muscular dystrophy, Bangladesh Medical Research Council Bulletin 2001:27.

Bonifati MD. Ruzza G. Bonometto P. Berardinelli A. Gorni K. Orcesi S. Lanzi G. Angelini C. A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve 2000:23:1344-1347.

Reitter B. Deflazacort vs. prednisone in Duchenne muscular dystrophy: trends of an ongoing study. Brain Dev. 1995:17(suppl):39-43.

Biggar WD. Gingras M. Fehlings DL.Harris VA. Steele CA. Deflazacort treatment of Duchenne muscular dystrophy. J Pediatr 2001:138(1):45-50.

Silversides CK. Webb GD. Harris VA. Biggar WD. Effects of Deflazacort on left ventricular function in patients with Duchenne muscular dystrophy. Am J Cardiol 2003:91(6):769-772.

Dubrovsky AL. De Vito E. Suarez A. Mesa LE. Pessolano F. Sobrino R. Deflazacort Treatment and Respiratory Function Duchenne Muscular Dystrophy. Neurology 1999:(suppl 2):52A:544.

Alman BA. Raza SN. and Biggar WD. Steroid treatment and the development of scoliosis in males with Duchenne muscular dystrophy. J Bone and Joint Surgery 2004:519-524.

Reitter B. Deflazacort vs. prednisone in Duchenne muscular dystrophy: trends of an ongoing study. Brain Dev 1995:17:(suppl):39-43.

Angelini C. Pegoraro E. Turella E. Intino MT. Pini A. Costa C. Deflazacort in Duchenne muscular dystrophy: study of long-term effect. Muscle Nerve 1994:17:386-391.

Mesa LE. Dubrovsky AL. Corderi J. Marco P. Flores D. Steroids in Duchenne muscular dystrophy – Deflazacort trial. Neuromuscular Disorders 1991:1:261-266.

Talim B. Malaguti C. Gnudi S. et al. Vertebral compression in Duchenne muscular dystrophy following deflazacort. Neuromuscular Disorders 2002:12:294-295.

Bothwell JE. Gordon KE. Dooley JM. MacSween J. Cummings EA. Salisbury. Vertebral fractures in boys with Duchenne muscular dystrophy. Clin Pediatr 2003:42(4):353-356.

Houde S. Filiatrault M. Daigneault P. Vanasse M. Dube J. Fournier A. Brousseau Y. Bérubé D. Lapierre G. Duchenne Muscular Dystrophy: An Eight-Year Experience with Deflazacort. J Neurorogical Sciences: Vol. 199. S1. July 15, 2002.

Fewtrell MS. Bone densitometry in children assessed by dual x-ray absorptiometry: uses and pitfalls. Arch Dis Child 2003:88:795-798.

Sievanen H. Koskue V. Rauhio A. Kannus P. Heinonen A. Vuori I. Peripheral quantitative computed tomography in human long bones: Evaluation of in vitro and in vivo precision. J Bone Miner Res 1998:13:871-882.

Levine MA. Biochemical markers of bone metabolism: application to understanding bone remodeling in children and adolescents. J Pediat Endocrinol Metab 2003:(suppl 16):3:661-672.

Homik J. Suarez-Almazor ME. Shea B. Cranney A. Wells G. Tugwell P. Calcium and vitamin D for corticosteroid-indicued osteoporosis. Cochrane Database Syst. Rev. 2000:(2):CD000952.

Ward K. Alsop C. Caulton J. Rubin C. Adams J. and Mughal Z. Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res 2004:Vol. 19, No.3.:360-369.

Fleisch H. Bisphosphonates in bone disease 4th Edition. Academic Press, San Diego 2000.

Brumsen C. Hamdy NAT. Papapoulos SE. Long-term effects of bisphosphonates on the growing skeleton. Medicine 1997:76:266-283.

Shaw NJ. Boivin CM. Crabtree NJ. Intravenous pamidronate in juvenile osteoporosis. Arch Dis Child 2000:83:143-145.

Shaw NJ. White CP. Fraser WD. Rosenbloom L. Osteopenia in cerebral palsy. Arch Dis Child 1994:71:235-238.

Bianchi ML. Cmiaz R, Badare M et al. Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children. Arthritis Rheum 2000:43:1960-1966.

Falcini F. Trapani S. Ermini M. Brandi ML. Intravenous administration of alendronate counteracts the in vivo effects of glucocorticoids on bone remodeling. Calcif Tissue Int 1996:58:166-169.

Glorieux FH. Bishop NJ. Plotkin H. Chabot G. Lanoue G. Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998:339:947-952.

Hawker GA. Ridout R. Harris VA. Chase CC. Fielding LJ and Biggar WD. Alendronate in the Treatment of Low Bone Mass in Steroid-Treated Boys with Duchenne Muscular Dystrophy. Arch. Phys. Medicine and Rehabilitation – in press.

Bachrach LK. Bare-Bones Fact-Children Are Not Small Adults. N Engl J Med 2004:351:924-926.

Leonard MB. Feldman HI. Shults J. Zemel BS. Foster BJ. and Stallings VA. Long-Term, High-Dose Glucocorticoids and Bone Mineral Content in Childhood Glucocorticoid-Sensitive Nephrotic Syndrome. N Engl J Med 2004:351:868-875.

WORKSHOP PARTICIPANTS
Dr. Ted Abresch
Dr. Laura Bachrach
Dr. Doug Biggar
Dr. Kate Bushby
Ms. Laura Case
Dr. Paula Clemens
Dr. John Day
Dr. Julie Dube
Dr. Victor Dubowitz
Dr. Michelle Eagle
Dr. Diana Escolar
Dr. Kevin Flanigan
Mrs. Pat Furlong
Dr. Rebecca Green
Dr. Richard Henderson
Dr. Andrew Hoey
Dr. Heidi Kalkwarf
Dr. Robert Leshner
Dr. Glen Nuckolls
Ms. Shree Pandya
Dr. Horacio Plotkin
Ms. Helen Posselt
Dr. David Saperstein
Dr. Laura Tosi
Dr. Joe Watt
Dr. Brenda Wong

Acknowledgement:

This workshop was made possible by the support of the Parent Project Muscular Dystrophy, USA.