Osteoporosis in Duchenne Muscular Dystrophy. Prasanth Surampudi, MD Associate Professor Division of Endocrinology UC Davis Medical Center, Davis, CA

Transcription

1 Osteoporosis in Duchenne Muscular Dystrophy Prasanth Surampudi, MD Associate Professor Division of Endocrinology UC Davis Medical Center, Davis, CA

2 OUTLINE Background: Bone Basics & Osteoporosis Bone Changes and Fracture Risk in Individuals with Duchenne Muscular Dystrophy Impact of Glucocorticoid Therapy on Bone in Individuals with Duchenne Muscular Dystrophy DMD Care Guidelines Screening of Bone Mineral Density and Fractures in Individuals with Duchenne Muscular Dystrophy Treatment of Osteoporosis in Individuals with Duchenne Muscular Dystrophy

3 Bone Basics: Important Cell Types Breaks down bone Builds bone Bone Growth: More Osteoblast Activity Activity of Activity of Activity of Activity of Bone Loss: More Osteoclast Activity Activity of Activity of Increasing Bone Mineral Density Maintenance of Bone Mineral Density Decreasing Bone Mineral Density

4 Bone Basics: Bone Structure Bone is made up of mainly collagen, calcium phosphate crystals Bone mass, can be reported as bone mineral content (BMC, (g)) or areal Bone Mineral Density (BMD (g/cm 2 )). Peak bone mass is achieved in the second or third decade, depending on the skeletal site 2 main types of Bone microarchitectures: Trabecular and Cortical Bone Trabecular bone Cortical Bone Trabecular bone is found in multiple areas including the Hip, Femoral neck, Vertebral body of spine Cortical bone is found in areas including the dense outer shafts of long bones Khosla S, Riggs BL, Atkinson EJ, Oberg AL, McDaniel LJ, Holets M, Peterson JM, Melton LJ 3 rd Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res Jan; 21(1): Silva MJ, Gibson LJ Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure. Bone Aug; 21(2):

5 Screening for Osteoporosis in Muscular Dystrophy Progressivemyopathy, a key risk factor for reduced bonestrength Lancet Neurol Apr; 17(4):

6 Bone Basics: Osteoporosis Osteoporosis Osteoporosis has been defined by the World Health Organization as a systemic disease characterized by Diffuse Bone loss with increased fracture risk Low Bone Mineral Density (BMD) can be detected Increased osteoclast activity, decreased osteoblast activity Deterioration of bone micro architecture seen in trabecular bone, cortical bone, and or both This leads to increased Skeletal fragility à Increased fracture risk

7 Bone Basics: Osteoporosis - Osteoporosis in children Osteoporosis Osteoporosis in children: Low Z score < - 2 and and a significant fracture history (2 or more long bone fractures before 10 years of age or 3 or more long bone fractures before 19 years of age) One or more vertebral fractures occurring in the absence of local disease or high-energy trauma

8 OUTLINE Background: Bone Basics & Osteoporosis Bone Changes and Fracture Risk in Individuals with Duchenne Muscular Dystrophy Impact of Glucocorticoid Therapy on Bone in Individuals with Duchenne Muscular Dystrophy DMD Care Guidelines Screening of Bone Mineral Density and Fractures in Individuals with Duchenne Muscular Dystrophy Treatment of Osteoporosis in Individuals with Duchenne Muscular Dystrophy

9 J Musculoskelet Neuronal Interact Dec; 16(4): Bone Mineral Density (BMD) Decreases in those with Muscular Dystrophy QUS Bone Health Data : Control vs Muscular Dystrophy T score distal radius Muscular Dystrophy T score Mid shaft tibia Muscular Dystrophy Muscular Dystrophy Muscular Dystrophy Z score distal radius Z score Mid shaft tibia Bone Density decreases in those with muscular dystrophy vs control ;

10 Bone Mineral Density (BMD) without Glucocorticoid Treatment Decreased BMD in Arm, Leg, Trunk Total Body BMD Total Body BMD w/o Head BMD is lower in DMD even without glucocorticoid treatment BMD BMD Decreased Muscle tension Head BMD Leg BMD BMD Arm BMD Trunk BMD BMD BMD Increased The inflammatory response (e.g. increased IL-6, IL-11, inhibin-βa and transforming growth factor-β, TNF alphawere increased. ) Increased activation of osteoclastogenesis by altered metabolism in the muscle (for example, activation of nuclear factor of NF κb pathways); King WN etalskeletal health in duchenne dystrophy: bone-size and Subcranial dual-energy x-ray absorptiometry analyses MUSCLE & NERVE 2014

11 Bone Mineral Density (BMD) Decreases in Both Ambulatory and in Non Ambulatory Lumbar BMD Decreases in both ambulatory and in non ambulatory Femur BMD Decreases in both ambulatory and in non ambulatory BMD Z Score BMD Z Score Ambulatory Non Ambulatory Ambulatory Non Ambulatory BMD Z score decreases more as individuals become non ambulatory (in Non Steroid and Steroid Exposed Patients) J Pediatr Orthop Jan-Feb;20(1):71-4.

12 J Musculoskelet Neuronal Interact Dec; 16(4): Bone Mineral Density (BMD) Decreases in Non Ambulatory > Ambulatory QUS Bone Health Data : Ambulatory vs Non Ambulatory T score distal radius T score Mid shaft tibia Ambulatory Ambulatory Non Ambulatory Non Ambulatory Ambulatory Ambulatory Non Ambulatory Non Ambulatory Z score distal radius Z score Mid shaft tibia Bone Density is worse in individuals with muscular dystrophy who become non ambulatory

13 Fracture Risk in DMD Fracture risk increase with Loss of Ambulation Fractures can happen in the long bones or spine and risk increases with age Fracture Probability % Mean age of loss of ambulation (11.2 yrs) Increased Fracture Probability Fracture Probability % Long Bones Vertebrae Developmental Medicine & Child Neurology 2002, 44: Journal of Child Neurology 2016, Vol. 31(9)

14 OUTLINE Background: Bone Basics & Osteoporosis Bone Changes and Fracture Risk in Individuals with Duchenne Muscular Dystrophy Impact of Glucocorticoid Therapy on Bone in Individuals with Duchenne Muscular Dystrophy DMD Care Guidelines Screening of Bone Mineral Density and Fractures in Individuals with Duchenne Muscular Dystrophy Treatment of Osteoporosis in Individuals with Duchenne Muscular Dystrophy

15 Time to Ambulation Improves with Glucocorticoid Therapy On steroids No steroids; No steroids; but used briefly in past J Neuromuscul Dis. 2017;4(4):

16 Spinal Alignment/Scoliosis Improves with Glucocorticoid Therapy Scoliosis Scoliosis Montreal Toronto Control Treated Control Treated Scoliosis 28/42 (67%) 10/37 (27%) 30/34 (90%) 4/40 (10%) Scoliosis surgery McAdam LC1, Mayo AL, Alman BA, Biggar WD. The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol May;31(1): Raudenbush BL1, Thirukumaran CP, Li Y, Sanders JO, Rubery PT, Mesfin A. Impact of a Comparative Study on the Management of Scoliosis in Duchenne Muscular Dystrophy: Are Corticosteroids Decreasing the Rate of Scoliosis Surgery in the United States? Spine (Phila Pa 1976) Sep;41(17 Koeks etal J Neuromuscul Dis. 2017;4(4):

17 Glucocorticoids decrease Osteoblast function and increase Osteoclast action Cooper MS Clinical Science 2004

18 Prolonged Glucocorticoid therapy Prednisone: 0.75 mg/kg/day DMD Deflazacort : 0.9 mg/kg/day Daily vs Intermittent therapy Despite Steroid therapy, there are continued changes to the bone

19 Glucocorticoid (Steroid) Induced Osteoporosis Glucocorticoid use can lead to the development of decreased BMD Glucocorticoid use can lead to the development of increased fracture risk BMD Z Scores Fracture Risk High Fracture Risk With Steroids & Prior Fractures Moderate Fracture Risk With Steroids Low Fracture Risk Miller PD Underdiagnoses and Undertreatment of Osteoporosis: The Battle to Be Won The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 3, 1 March 2016, Pages Klotzbuecher CM, et al. J Bone Miner Res. 2000;15:721.. L. Bianchi etalbone mineral density and bone metabolism in Duchenne muscular dystrophy Osteoporosis Internationa September 2003, Volume 14, Issue 9, pp

20 DMD: Risk of Low Trauma Fractures Low-trauma fractures are defined as those occurring from a standing height or less. A vertebral fracture that occurs without major trauma is an important indication of abnormal bone fragility. A Long fracture that occurs without major trauma is an important indication of abnormal bone fragility.

21 DMD: Risk of Fractures A large % with DMD have low-trauma extremity fractures (usually the distal femur, tibia, or fibula), while up to 30% develop symptomatic vertebral fractures Boys with glucocorticoid-treated DMD frequently develop osteoporosis, which manifests as low-trauma vertebral or long-bone fractures Simm PJ etal Consensus guidelines on the use of bisphosphonate therapy in children and adolescents J Paediatr Child Health Mar;54(3):

22 DMD: Risk of Fractures DMD and Osteoporosis ~ 20 60% of boys with DMD have low-trauma extremity fractures (usually the distal femur, tibia, or fibula), Death due to fat embolism syndrome after long-bone fractures has also been reported in boys with DMD Vertebral Fractures: true prevalence is probably higher than existing reports suggest (? Up to 40 to 50%?) ~ 30% develop symptomatic vertebral fractures Vertebral fractures are frequently asymptomatic Simm PJ etal Consensus guidelines on the use of bisphosphonate therapy in children and adolescents J Paediatr Child Health Mar;54(3):

23 Fracture Risk in DMD with and without Glucocorticoid Treatment Risk of fracture Vertebral fractures Long bone fractures. 20 to 30% by ages to 10 to 11 NO Steroid Therapy Steroid Therapy Steroid Therapy NO Steroid Therapy Glucocorticoid Tx increases long bone fracture risk but lowers vertebral fracture risk; however risk for vertebral fractures is still high with glucocorticoid therapy Perera N eta Fracture in Duchenne Muscular Dystrophy: Natural History and Vitamin D Deficiency. J Child Neurol Aug;31(9): J Bone Joint Surg Am Mar;86-A(3):

24 Fracture Risk in DMD with Glucocorticoid Treatment Avg time of fracture on glucocorticoids Long bone 4 yrs 10 mo Vertebral: 6 yrs 7 mo risk of fracture Long bone > Vertebral bone; But Risk nearly equivalent by age 12 Perera N eta Fracture in Duchenne Muscular Dystrophy: Natural History and Vitamin D Deficiency. J Child Neurol Aug;31(9): J Bone Joint Surg Am Mar;86-A(3):

25 Fracture Risk in DMD with Glucocorticoid Treatment also Increased in Non Ambulatory A Retrospective Study of patients with wheel chair use 33% had at least 1 fracture 249 of 747 cases. Full-time wheelchair use increased the risk of first fracture by 75% for every 3 months of use corticosteroid use, bisphosphonate use, and calcium/vitamin D use did not significantly affect risk in the final adjusted model. Probability of Not Experiencing a fracture Despite Glucocorticoids, there is an increased risk of experiencing a fracture in non ambulatory patients James KA etal Risk Factors for First Fractures Among Males With Duchenne or Becker Muscular Dystrophy. J Pediatr Orthop Sep;35(6):640-4.

26 Bothwell JE Vertebral Fractures in Boys with Duchenne Muscular Dystrophy Clin Pediatr (Phila) May;42(4): Singh A etal. Vertebral Fractures in Duchenne Muscular Dystrophy Patients Managed With Deflazacort. J Pediatr Orthop Jul;38(6) While overall time to Vertebral Fracture is lower with Glucocorticoids- Vertebral Fracture do occur on Glucocorticoids A latency period of 40 months after commencement of steroids occurred before the first vertebral fracture appeared. However, by 100 months of treatment approximately 75% had sustained a vertebral fracture. FX risk increases with Steroid use FX risk increases with Steroid use FX risk increases with age ; > 10 FX risk increases with age ; > 10

27 Figure 2 Summary of Glucocorticoid Use & Outcomes Early GC use Late GC use Late GC use Time of Ambulation Early GC use Risk of Scoliosis Overall Risk of Fx Late GC use Early GC use Kim S1, Zhu Y2, Romitti PA2, Fox DJ3, Sheehan DW4, Valdez R5, Matthews D6, Barber BJ7; MD STARnet. Associations between timing of corticosteroid treatment initiation and clinical outcomes in Duchenne muscular dystrophy. Neuromuscul Disord Aug;27(8):

28 Figure 2 Growth Delay Due to Glucocorticoids Glucocorticoids have a direct, inhibitory effect on the growth plate Impairment affected by dose & longer duration of glucocorticoid use prednisone-equivalent dose was 0.5 ± 0.6 mg/kg per day most pronounced when glucocorticoids are administered daily a larger number can have growth of less than 4 cm/year David B. Allen, Inhaled Corticosteroids and Growth: Still an Issue after All These Years 2015 Volume 166, Issue 2, Pages McAdam LC1, Mayo AL, Alman BA, Biggar WD. The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol May;31(1):16-20.

29 Steroid Induced Complications

30 Usage of corticosteroids In DMD: In many patients but not all Global TREAT-NMD DMD database. Ryder S1etal. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis Apr 26;12(1):79. Koeks etal J Neuromuscul Dis. 2017;4(4):

31 OUTLINE Background: Bone Basics & Osteoporosis Bone Changes and Fracture Risk in Individuals with Duchenne Muscular Dystrophy Impact of Glucocorticoid Therapy on Bone in Individuals with Duchenne Muscular Dystrophy DMD Care Guidelines Screening of Bone Mineral Density and Fractures in Individuals with Duchenne Muscular Dystrophy Treatment of Osteoporosis in Individuals with Duchenne Muscular Dystrophy

32 Screening of Bone Mineral Density and Fractures in Individuals with Duchenne Muscular Dystrophy PHYSICAL EXAM DXA (BONE DENSITY) LABS X-Rays

33 Screening for Osteoporosis: DMD Care Guidelines 2018 & Labs David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

34 Screening for Osteoporosis: DXA David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

35 Bone Basics: Dual Energy X Ray Absorptiometry (DXA) The National Osteoporosis Foundation indications for DXA in children include: systemic long-term steroids, chronic inflammatory conditions, hypogonadism, prolonged immobilization, recurrent low trauma fractures, and apparent osteopenia on radiographs Baseline DXA examination for patients for whom systemic corticosteroids will be used for more than 2 months or who are at significant risk of osteoporotic fracture DXA of the lumbar spine and hip for pediatric patients with a significant risk factor for osteoporosis

36 Bone Basics: Dual Energy X Ray Absorptiometry (DXA) Measure Bone Mineral Density DXA can report T score T-score- BMD in individuals who have achieved peak bone mass matched for sex and ethnicity (age > 20) not used in children as BMD has yet to peak ( T- scores which compare the patient s BMD with that of a healthy young adult should not be used before 20 years of age) DXA can report Z score Z-score- BMD in individuals age matched, sex matched, race matched; can be used in children < 20 yrs of age Reduced BMD also is associated with increased fracture risk in children and teenagers, but the data are not sufficient to establish the diagnosis of osteoporosis on the basis of bone densitometry criteria alone Pediatrics. 2016;138(4):e

37 Bone Basics: Dual Energy X Ray Absorptiometry (DXA) Measure Bone Mineral Density Z score Normal Category At risk for low bone mineral density or bone mineral content for chronologic age) Low bone mineral density or bone mineral content for chronologic age Z-score (children) O and above -1.0 and and below can be used in children < 20 yrs of age T score Category T-score (adults) Normal -1.0 and above Low bone mass (osteopenia) Between -1.0 to -2.5 can be used in > 20 yrs of age Osteoporosis -2.5 and below Pediatrics. 2016;138(4):e

38 Diagnosis of Osteoporosis: DMD Care Guidelines 2018 & DXA The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric (DXA) criteria alone. In the absence of vertebral compression (crush) fractures, the diagnosis of osteoporosis is indicated by the presence of both fracture history DXA BMD Z-score A BMC/BMD Z-score > -2.0 does not preclude the possibility of skeletal fragility and increased fracture risk. Although BMD Z scores are no longer at the forefront of diagnosis, they remain useful to determine the overall trajectory of bone health in an individual child and thereby guide frequency of lateral spine radiographs during the monitoring phase David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

39 Screening for Osteoporosis: X -RAYS David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

40 Screening for Osteoporosis: DMD Care Guidelines 2018: X-Rays David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

41 Frequency and Location of Vertebral Fractures In Boys with DMD (Pre-bisphosphonate Treatment) Wedge Crush Biconcave Wedge fractures are most common In Mid-thoracic region T7 T9 Anterior wedge (thoracic) more common In Thoracolumbar junction T12 L1 more common Crush/Symmetric compression (T-L junction) more common In Lumbar region Biconcave (upper lumbar) more common Sbrocchi AM1, Rauch F, Jacob P, McCormick A, McMillan HJ, Matzinger MA, Ward LM. The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with Duchenne muscular dystrophy. Osteoporos Int Nov;23(11): (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014) Wong C, Girt M Vertebral compressions fractures: a review of current management and multimodal therapy Multidiscip Health 2013; 6:205-21

42 Vertebral Fractures In Boys with DMD Vertebral fractures can occur irrespective of Z score Vertebral fractures can occur in children who have BMD Z scores < 2 SD Vertebral fractures can occur in children who have BMD Z scores > 2 SD This observation prompted the International Society for Clinical Densitometry to revise the definition of osteoporosis in a child with a low-trauma vertebral fracture sothat cutoff criteria based on BMD Z scores are no longer required to make the diagnosis of osteoporosis

43 Femur Fractures Femur fractures can occur in children who have BMD Z scores < 2 SD 15% of children with neuromuscular disorders and extremity fractures will have BMD Z scores for the distal femur > 2 SD I.e. need X- rays David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

44 Screening for Osteoporosis: DMD Care Guidelines 2018 & X-Rays No published studies of DMD or any osteoporotic condition of childhood have assessed the safety and efficacy of medical therapy in preventingthe first-ever fracture Untreated, vertebral fractures can lead to chronic back pain and spine deformity, Leg fractures can cause premature, permanent loss of ambulation David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

45 OUTLINE Background: Bone Basics & Osteoporosis Bone Changes and Fracture Risk in Individuals with Duchenne Muscular Dystrophy Impact of Glucocorticoid Therapy on Bone in Individuals with Duchenne Muscular Dystrophy DMD Care Guidelines Screening of Bone Mineral Density and Fractures in Individuals with Duchenne Muscular Dystrophy Treatment of Osteoporosis in Individuals with Duchenne Muscular Dystrophy

46 Intervention: Calcium & Vitamin D Treatment Adequate calcium and vitamin D intake is important for normal bone mineral deposition. Many boys with DMD are vitamin D insufficient or deficient Adequate calcium and vitamin D intake is important for normal bone mineral deposition. With Calcium + vitamin D in boys with DMD, there were increases in BMD after 12 months.

47 Intervention: Calcium & Vitamin D Treatment I use 1000 IU of vitamin D3 N. H. Golden, S. A. Abrams, S. R. Daniels et al., Optimizing bone health in children and adolescents, Pediatrics, vol. 134, no 4, pp. e1229 e1243, 2014.

48 Treatment of Osteoporosis: DMD Care Guidelines Bisphosphonates Lancet Neurol Apr; 17(4):

49 Treatment of Osteoporosis: Bisphosphonates Pamidronate or Zolendronate can be used Simm PJ etal Consensus guidelines on the use of bisphosphonate therapy in children and adolescents J Paediatr Child Health Mar;54(3):

50 Treatment of Osteoporosis in DMD: DMD Care Guidelines 2018 DMD and Osteoporosis No published studies of DMD have assessed the safety and efficacy of medical therapy in preventing the first-ever fracture. Current standard is to identify and treat early indications of bone fragility (eg, vertebral fractures) in individuals with chronic illnesses who have little possibility of recovery. Current standard is secondary prevention approach has the goal of mitigating osteoporosis progression and promoting recovery among patients presenting with early, Simm PJ etal Consensus guidelines on the use of bisphosphonate therapy in children and adolescents J Paediatr Child Health Mar;54(3): David J Birnkrant eal Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management Lancet Neurology 2018

51 Treatment of Osteoporosis: DMD Care Guidelines 2018 Indications for treatment with intravenous bisphosphonate the presence of low-trauma vertebral fractures Previously, only back pain or spine deformity prompted a radiograph to identify vertebral fractures necessitating bisphosphonate therapy. Now asymptomatic but nevertheless advanced (ie, moderate and severe) vertebral fractures reshaping of previously fractured vertebral bodies have been reported in boys with DMD the presence of low-trauma long-bone fractures We endorse the use of intravenous (and not oral) bisphosphonates as firstline therapy for the treatment of osteoporosis in patients with DMD

52 Extra Slides

53 Scoliosis in DMD: Impact of Glucocorticoids Patients not treated with glucocorticoids have a 90% chance of developing significant progressive scoliosis In Non Steroid Tx: Scoliosis 10 occurred in 85 of 88 patients (97%), 20 in 78 of 88 (89%) and 30 in 66 of 88 patients (75%) With Steroid Tx : Daily glucocorticoid treatment has been shown to reduce the risk of scoliosis; Steroid Tx No Steroid Tx Less Scoliosis More Scoliosis Lancet Neurol Apr; 17(4): J Bone Joint Surg Am Mar;86-A(3):

54 Scoliosis in DMD: Monitoring Monitoring for scoliosis Ambulatory phase, with spinal radiography warranted only if scoliosis is observed. In the non-ambulatory phase, clinical assessment for scoliosis is essential at each visit. Baseline Spinal radiography I for all patients around the time that wheelchair dependency begins with a sitting AP full-spine radiograph and LP film. An AP spinal radiograph : annually for curves of less than An AP spinal radiograph every 6 months for curves of more than 20, irrespective of glucocorticoid treatment, up to skeletal maturity Lancet Neurol Apr; 17(4):

55 Spinal Alignment/Scoliosis Improves with Glucocorticoid Therapy Steroids Decrease Scoliosis Surgeries Scoliosis Surgeries with all GC Scoliosis Surgeries With Time Scoliosis Surgeries With Time McAdam LC1, Mayo AL, Alman BA, Biggar WD. The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol May;31(1): Raudenbush BL1, Thirukumaran CP, Li Y, Sanders JO, Rubery PT, Mesfin A. Impact of a Comparative Study on the Management of Scoliosis in Duchenne Muscular Dystrophy: Are Corticosteroids Decreasing the Rate of Scoliosis Surgery in the United States? Spine (Phila Pa 1976) Sep;41(17 Koeks etal J Neuromuscul Dis. 2017;4(4): Gloss D1, Moxley RT 3rd1, Ashwal S1, Oskoui M1. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology Feb 2;86(5):

56 Scoliosis in DMD: Treatment Tx for scoliosis Not on Glucocorticoids Posterior spinal fusion is warranted only in non-ambulatory patients who have spinal curvature of more than 20, and have yet to reach skeletal maturity On Glucocorticoids Posterior spinal fusion is warranted if curve progression continues and is associated with vertebral fractures and pain after optimization of medical therapy to strengthen the bones, irrespective of skeletal maturation. Lancet Neurol Apr; 17(4):

57 Trials with Bisphosphonate Therapy in DMD Study Year Study type Patient number Houston et al. [52] 2014 Retrospective cohort Steroids were on prednisone or deflazacort Bisphosphona te Alendronate PO Mean Age at Bisphosphona te Initiation 12 years old (no range given) Results Z-score trended up at the hip with alendronate, but it is not statistically significant Comments 10 did not receive alendronate, varying dosages of alendronate used Sbrocchi et al. [53] 2012 Retrospective observational Int J Endocrinol. 2015; All but 1 were reported as prednisone equivalents Pamidronate 11.6 years old IV (range: mg/kg/year 14.3 years or zoledronic old) acid IV 0.1 mg/kg/yea r Improved back pain and stabilization to improvement in vertebral height ratios for the previously fractured vertebrae Only patients with vertebral fractures were included in the study

58 Trials with Bisphosphonate Therapy in DMD Gordon et al. [54] 2011 Retrospective observational 44 5 prednisone only; 13 changed from prednisone to deflazacort; 26 deflazacort only 11 used pamidronate only; 1 changed from pamidronate to alendronate; 3 alendronate only; 1 clodronate only 12.5 years old (range: 7 23 years old) Survival curve showed improvement in survival rate (P = 0.005, logrank test); also, possible therapy duration effect could be present (P = 0.007, log-rank test) Pamidronate was IV; alendronate was PO; clodronate was PO Atance et al. [55] 2011 Case reports 3 2 on deflazacort Int J Endocrinol. 2015;2015 Alendronate 10 mg daily PO 11.4 years old (range: years old) Reduced back pain and improved BMD Only 3 patients were reported

59 Trials with Bisphosphonate Therapy in DMD Hawker et al. [56] 2005 Before-after trial 23 All on deflazacort Alendronate 10.8 years 0.08 mg/kg/d old (range: ay PO years old) Positive effect on BMD and Z- scores, better BMD outcome when given early in the course of disease Also received 750 mg daily calcium and 1000 IU vitamin D Int J Endocrinol. 2015;2015

60 Trials with Bisphosphonate Therapy in DMD randomized participants with a spine Z-score less than -1.0 to risedronate plus calcium and vitamin Dà improved BMD in spine & Whole body Median spine Z- score (range) Median wholebody Z-score (range) Risedronate (plus calcium and vitamin D supplementation) Control (calcium and vitamin D supplementation alone) Baseline 12-month Baseline 12 months (-1.2 to - 3.5) (-0.5 to 2.7)* -0.8 (-1.7 to 0) -2.2 (-4.1 to -1.2) -1.6 (-8.4 to -0.8) 1.3 (-1.0 to 2.5) -1.2 (-1.6 to 4.7) -0.8 (-3.1 to 3) Bell JM etal Interventions to prevent and treat corticosteroid-induced osteoporosis and prevent osteoporotic fractures in Duchenne muscular dystrophy. Cochrane Database Syst Rev Jan 24; McSweeney N, McKenna M, Van Der Kamp S, Kilbane M, McDonnell C, Murphy N, et al. Risedronate use in Duchenne muscular dystrophy: a pilot randomised control trial. Hormone Research in Paediatrics 2014;82(Suppl 1): Bianchi ML, Vai S, Morandi L, Baranello G, Pasanisi B, Rubin C. Effects of low-magnitude high-frequency vibration on bone density, bone resorption and muscular strength in ambulant children affected by Duchenne muscular dystrophy. Journal of Bone and Mineral Research 2013;28