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Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy
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Neuromuscular Disorders 22 (2012) 1040–1045 www.elsevier.com/locate/nmd
Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy A.L. Mayo a,⇑, B.C. Craven a,b, L.C. McAdam c,d, W.D. Biggar c,d a b
Department of Medicine, Division of Physiatry, University of Toronto, Canada Toronto Rehabilitation Institute – University Health Network, Toronto, Canada c Department of Paediatrics, University of Toronto, Canada d Holland Bloorview Kids Rehabilitation Hospital, Toronto, Canada Received 5 June 2012; accepted 29 June 2012
Abstract Quality of life in Duchenne Muscular Dystrophy (DMD) has improved significantly with corticosteroid treatment. However, corticosteroids decrease bone mass and increase vertebral fragility fracture risk. We report on bone health in 39 boys with DMD on long-term deflazacort (0.9 mg/kg/day) therapy. Bone health was defined by lumbar (L1–L4) bone mineral density (BMD), long-bone and/or symptomatic vertebral fractures. Lumbar BMD was reported as height-adjusted Z-scores at initiation of deflazacort (T0) and 1–2 year intervals thereafter. Subcapital body fat percentage and ambulatory status were recorded. At T0, 39 boys, aged 6.6 ± 1.6 years had height-adjusted BMD Z-score 0.5 ± 0.8, and 23.5 ± 5.0% body fat. Height-adjusted Z-scores remained stable with years of deflazacort until loss of ambulation and accrual of body fat. Nine long-bone fractures occurred in eight ambulating boys, two before T0. Seven vertebral fractures occurred in six non-ambulatory boys after P5 years of deflazacort with height-adjusted Z-score 1.8 ± 0.7, and 47.8 ± 12% body fat. Bone health in DMD is influenced by disease progression, corticosteroids, BMD Z-scores and fat mass accumulation. Adjustments for short stature must be considered during BMD interpretation. Percent body fat and ambulatory status are useful bone health indicators. Routine use of height adjusted Z-scores is advocated for use in routine clinical practice. Ó 2012 Elsevier B.V. All rights reserved. Keywords: Duchenne Muscular Dystrophy; Deflazacort; Bone mineral density; Fractures
1. Introduction Duchenne Muscular Dystrophy (DMD), an x-linked recessive disorder, occurs in approximately one in 3500 live male births. DMD is associated with progressive skeletal and cardiac muscle weakness. Males typically present with proximal muscle weakness at 3–6 years of age and lose ambulation by age 7–12 years (average age 10) [1,2]. Death usually occurs during the 2nd or 3rd decade due to cardiac and/or respiratory failure. Life expectancy has been increased with improved cardiorespiratory care [1,3,4].
⇑ Corresponding author. Present address: 55 Ian Drive, Keswick ON, Canada L4P 4G9. Tel.: +1 905 252 8404. E-mail address: [email protected] (A.L. Mayo).
0960-8966/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.nmd.2012.06.354
With daily corticosteroid treatment, boys ambulate 3–5 years longer, have preserved cardiac and pulmonary function and significantly reduced scoliosis [1,2,5]. Prednisone (0.75 mg/kg/day) and deflazacort, an oxazolone derivative of prednisolone (0.9 mg/kg/day) are the most frequently used corticosteroids to treat DMD [1,6]. Side effects of corticosteroids can be significant and include excessive weight gain, short stature, behavioural issues, posterior capsular cataracts, delayed puberty and reduced bone mass [2,5–9]. Deflazacort, is reported to be less detrimental to trabecular bone than prednisone [10]. Boys with DMD have at least two major risk factors for compromised bone health; a disruption of the muscle-bone unit and treatment with corticosteroids [11,12]. Fractures in corticosteroid treated DMD boys most frequently occur
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Table 1 Changes in lumbar spine BMD Z-scores and body composition with years of deflazacort therapy among BMD boys.
Boys (N) Age (years) Height Z-score (mean ± SD) Age-based BMD Z-score (mean ± SD) Height-adjusted BMD Z-score (mean ± SD) Body fat% (mean ± SD) BMI (mean ± SD) Independent ambulation (N, %) * ** ¥
T0
Years of deflazacort therapy 1–2 (1.6 ± 0.5)
3–4 (3.4 ± 0.6)
5–6 (5.2 ± 0.5)
7–8 (7.1 ± 0.5)
39 6.6 ± 1.6 1.0 ± 1.3 1.1 ± 0.8¥ 0.5 ± 0.8 23.5 ± 5.0 16.6 ± 1.8 39/39 (100%)
36 8.0 ± 1.5 1.6 ± 0.9* 1.5 ± 1.0*,¥ 0.7 ± 0.9 27.5 ± 10.7* 18.8 ± 3.2* 36/36 (100%)
24 10.3 ± 1.5 2.1 ± 1.0* 1.8 ± 0.9¥ 0.7 ± 1.1 39.8 ± 9.6** 22.1 ± 3.6** 22/24 (96%)
25 11.8 ± 1.8 2.4 ± 1.1 2.4.±1.3 ¥ 0.9 ± 1.2 43.2 ± 11.8 22.9 ± 5.4 21/25 (88%)
13 14.2 ± 1.7 2.7 ± 0.7 3.6 ± 1.1**,¥ 1.8 ± 0.8* 51.1 ± 10.6* 23.2 ± 4.1 5/13 (38%)
p < 0.05. p < 0.001 significance between previous value and follow-up value. p < 0.001 significance between age and Ht-Z based lumbar BMD Z-score.
Table 2 Long-bone and vertebral fracture demographics and DXA results.
Number of fractures Age at fracture Height Z-score Years on deflazacort Age-based BMD Z-score Height-adjusted BMD Z-score Body fat% BMI * **
Long-bone fractures
Vertebral fractures
9 9.0 ± 3.0 1.4 ± 1.2 2.8 ± 2.1 2.3 ± 0.7 1.5 ± 0.6
7 14.1 ± 2.4* 3.2 ± 0.8* 7.5 ± 1.8** 3.5 ± 0.7* 1.8 ± 0.7
33 ± 14.2 19.7 ± 5.5
47.8 ± 12.0* 23.1 ± 4.1
p < 0.05. p < 0.001 significance between long-bone and vertebral fracture values.
in the distal femur, proximal tibia and vertebrae, all areas of high trabecular bone content [8,13,14]. In comparison with steroid-naive DMD boys, corticosteroids are reported to increase vertebral fracture risk but not long-bone fracture risk [2,7,9,15–18]. There is currently no published international consensus for the management of bone health among boys with DMD. However, recent international workshops have focused on the development of recommendations for the optimal management of bone health in boys with DMD on corticosteroids [6,19–21]. Vitamin D and calcium supplements have been shown to benefit the preservation of bone mass among DMD boys [22]. Recommendations for the use of bisphosphonate therapy to treat DMD boys with low bone mass and high fracture risk are evolving [6,21]. The primary objective of this study is to describe and compare the changes in lumbar spine (L1–L4) BMD with years of deflazacort therapy using both age-based and height-adjusted Z-scores. The secondary objectives of this study are to describe the frequency and site of fractures in a cohort of boys with DMD treated with daily deflazacort; and to explore the associations between fracture frequency, duration of deflazacort therapy, body fat composition, ambulatory status, and lumbar bone mineral density.
2. Patients and methods Clinical data were obtained prospectively from a convenience sample of 39 boys with DMD on deflazacort treatment, followed at Holland Bloorview Kids Rehabilitation Hospital’s multidisciplinary neuromuscular clinic between January 2001 and December 2011. All patients met the following diagnostic criteria for DMD: (1) onset of weakness prior to age 5, (2) male, (3) proximal muscle weakness, (4) elevated serum creatinine kinase, and (5) DMD confirmed through muscle biopsy and/or dystrophin gene analyses. All boys initiated deflazacort while still ambulatory and before experiencing significant loss of muscle function as evidenced by increased falls, difficulty with rising from supine to standing or difficulty climbing stairs. This was usually between 4 and 6 years of age. The initial dose of deflazacort was 0.9 mg/kg/day. The dose of deflazacort was adjusted with weight gain to a maximum of 39 mg/day. The mean dose at 10 years of age was 0.8 ± 0.18 mg/kg/ day, at 15 years was 0.55 ± 0.09 mg/kg/day and 18 years was 0.5 ± 0.2 mg/kg/day [2]. Supplements of elemental calcium (750 mg) and vitamin D (1000 IU) were advised. Prior to initiation of deflazacort, serum vitamin D levels were performed and if low, 2000 IU of vitamin D were recommended. BMD was routinely assessed before deflazacort was started (T0) and every 1–2 years thereafter. Patient monitoring was done every 4 months using a standard clinical protocol [2]. Boys were independently evaluated by a clinic nurse, physiotherapist, occupational therapist, respiratory therapist, and physician at each visit. Clinic visits included documentation of height, weight, ambulatory status, fractures, and adherence to calcium and vitamin D supplements. Height for ambulatory boys was measured to the nearest 0.1 centimetre using a stadiometer. Height for non-ambulatory boys was calculated based on their measured ulnar length from the tip of the ulnar styloid to the olecranon [23]. BMI was calculated as weight/height2 (kg/m2). Loss of ambulation was defined as the inability to walk 10 m independently on a level floor without gait aids.
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Only symptomatic vertebral fractures were recorded. Symptoms included a history of back pain when changing position, localized back pain when driving over minor bumps in their power wheelchair, or riding on the school bus, and localized pain on palpation over the vertebral body and spinous process. Spine X-rays were only ordered for boys reporting vertebral back pain or progressive scoliosis noted on physical examination. Spine X-rays were performed at Holland Bloorview by the same qualified X-ray technician. The X-rays were reviewed by the same radiologist using the semi-quantitative method as described by Genant et al. [24]. Vertebrae were graded on visual inspection as normal (grade 0), mildly deformed with 20–25% reduction of anterior, middle and/or posterior height (grade 1), moderately deformed with 25–40% reduction of height (grade 2) or severely deformed with approximately 40% reduction in height in any height and area. A vertebral body was diagnosed as fracture if graded 1 or higher. Vertebral fractures were classified as wedge, biconcave and/or crush deformity based on the atlas by Genant et al. [24]. Bone mineral density (BMD) testing was performed at Toronto Rehabilitation Institute using a Hologic QDR 4500W (Waltham, MA, USA) densitometer. The change in Z-scores with years of deflazacort treatment was evaluated from baseline (T0) and subsequently over serial scans. Scans of the whole body and lumbar (L1–L4) regions were acquired in array mode and analyzed based on the manufacturers’ guidelines for pediatric total body less head and lumbar spine assessment using the Hologic AP spine software, version 12.3, respectively. Lumbar BMD (g/cm2) and body fat% from total body less head DXA scans were recorded. The coefficients of variation for the scanner were within acceptable limits as defined by the manufacturer. All DXA scans were done using the same densitometer and by one of two ISCD certified DXA technologists. Lumbar BMD results were compared to an updated 2011 reference curve for age, sex and ethnicity matched healthy boys to obtain the age-based Z-score (SD units above or below the mean) [25]. Due to the boys short stature and smaller bone volumes, their DXA scans were also analyzed adjusting for both age and height [22,26] The height Z-score (Ht-Z) for the boys’ chronological age was calculated using the Epi Info Nutrition Calculator provided free online by the US Centres for Disease and Prevention website (http://www.cdc.gov/epiiinfo). This Ht-Z score was then used in the equations described by Zemel et al. to calculate a height-adjusted BMD Z-score [25]. Descriptive statistics (mean and SD) were performed on the BMD age-based and height-adjusted Z-scores and body fat at deflazacort initiation (T0) and then with years of therapy. A Student’s t-test was performed on the agebased and height-adjusted lumbar Z-scores for statistically significant differences between these mean values. Fracture site was reported as long-bone (upper or lower extremity) and vertebral. Demographic and BMD values
for boys with and without fractures were analyzed with descriptive statistics (mean ± SD, Student’s t-test) for associations between fractures and age, duration of deflazacort treatment, ambulatory status, body fat% and BMI. Ethics approval was obtained through Holland Bloorview Kids Rehabilitation Hospital. The clinical data presented herein were obtained prospectively via chart abstraction from Holland Bloorview Kids Rehabilitation Hospital’s clinical DMD database, with participant/parent consent/assent as appropriate for participation. 3. Results The 39 boys were 6.6 ± 1.6 years old and all independently ambulating when deflazacort was started (T0). At the end of the follow-up period (December 2011), there were 38 boys aged 12.8 ± 3.6 years old with 6.6 ± 2.8 years of deflazacort treatment (range 1.4–11.0 years). Twentyeight of the 38 boys were still ambulating independently. When the boys were older than 12 years, puberty was delayed by three or more years. One of the 39 boys died during the follow-up period of suspected fat embolism syndrome at age 14 following a minor fall. During the year of his death, he was non-ambulatory with height-adjusted lumbar BMD Z-score of 2.8, age-based lumbar Z-score of 4.6, body fat of 58.6% and BMI 27.3. The changes in lumbar spine BMD over time are expressed both as the age-based and the height-adjusted Z-scores and are summarized in Table 1. The boys entered the study at different ages and times during the study period, so the denominator for the number of scans and years on deflazacort varies across time points. We have reported the denominator for each time period. At T0, 39 of 39 of the boys were aged 6.6 ± 1.6 years with a height Z-score of 1.0 ± 1.3 SD below age matched boys. Their T0 age-based lumbar BMD Z-score was 1.1 ± 0.8 and height-adjusted BMD Z-score was 0.5 ± 0.8. Thirty-six of the 39 boys, aged 8.0 ± 1.5 years had scans after 1.6 ± 0.5 years of deflazacort. They were of shorter stature with height Z-score 1.6 ± 0.9 vs 1.0 ± 1.3 at T0 (p < 0.05). Their age-based BMD Z-score had significantly decreased to 1.5 ± 1.0 (p < 0.05). In contrast, the heightadjusted BMD Z-score was not significantly decreased at 0.7 ± 0.9. Twenty-four of the 39 boys, aged 10.3 ± 1.5 years had scans after 3.4 ± 0.6 years of deflazacort. They were significantly shorter height Z-score of 2.1 ± 1.0 vs 1.6 ± 0.9 (p < 0.05). Their age-based BMD Z-score had decreased to 1.8 ± 0.9 and height-adjusted BMD Z-score was unchanged ( 0.7 ± 1.1). Twenty-five of the 39 boys, aged 11.8 ± 1.8 years had scans after 5.2 ± 0.5 years of deflazacort. Their height Zscore had further decreased to 2.4 ± 1.1. Their age-based BMD Z-score further decreased to 2.4 ± 1.3 and heightadjusted BMD Z-score was slightly decreased, at 0.9 ± 1.2.
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Thirteen of the 39 boys, aged 14.2 ± 1.7 years had scans after 7.1 ± 0.5 years of deflazacort. Their height Z-score was low, 2.7 ± 0.7. Their age-based BMD Z-score was significantly decreased, 3.6 ± 1.1 (p < 0.001) as was the height-adjusted BMD Z-score of 1.8 ± 0.8 (p < 0.05). At T0 and for all time points, the age-based BMD Z-score was significantly decreased (p < 0.001) than the height-adjusted BMD Z-score. Independent ambulation was preserved for the majority of the boys, 21 of 25 (88%) with more than 5 but less than 7 years of therapy. Of the boys with over 7 years of therapy, only five of 13 (38%) were independent ambulators (A). The eight boys that were non-ambulatory had significantly lower (p < 0.05) age-based BMD Z-score of 4.2 ± 0.6 than the five ambulatory boys age-based Z-score of 3.0 ± 1.0. The height-adjusted BMD Z-score of the non-ambulatory boys, 2.2 ± 0.6 was clinically lower than the ambulating boys height-adjusted Z-score of 1.2 ± 0.9 but did not reach statistical significance (p = 0.07). The eight nonambulating boys had slightly but not significantly higher (p = 0.26) body fat percentage of 55.5 ± 2.8 to five ambulatory boys with a body fat 47.6 ± 14.5%. During the study period, there were nine long-bone fragility fractures in eight of the 39 boys (21%); three upper extremity and six lower extremity fractures. Two boys had an upper extremity fracture before T0, and one of these boys subsequently had a lower extremity fracture while on deflazacort. All long-bone fractures occurred in independently ambulating boys. Three of the six boys (50%) lost independent ambulation at ages 10, 11 and 15 years old when they had a leg fracture. Six boys complained of vertebral back pain and had vertebral fractures confirmed on spine X-ray. One boy had a single lumbar vertebral fracture; all other boys had three or more vertebral fractures in the lower thoracic and upper lumbar regions. All vertebral fractures occurred in nonambulatory boys. Two of the six boys had a long-bone fracture prior to their vertebral fracture. The vertebral fractures were all anterior wedge and biconcave fractures with no radiculopathy or change in spinal alignment. DXA scan data at time of fracture for the long-bone and vertebral fractures are summarized in Table 2. Long-bone fractures occurred in younger boys mean age 9.0 ± 3.0 years, falling while independently ambulating and after 2.8 ± 2.1 years of deflazacort therapy. Vertebral fractures occurred in older, non-ambulatory boys, age 14.1 ± 2.4 years. All boys with vertebral fractures had over 5 years of deflazacort. The age-based BMD Z-scores for the boys with vertebral fractures were significantly lower (p < 0.05) than boys with long-bone fractures. All vertebral fractures occurred at an age-based BMD Z-score of 6 2.5 and at height-adjusted BMD Z-score 1.8 ± 0.7. The vertebral fractures occurred at significantly higher (p < 0.05) body fat percentage, 47.8 ± 12% than the long-bone fractures, 33 ± 14.2%. Five of the seven vertebral fractures occurred in boys with P50% body fat. BMI was on average, normal at time of vertebral fracture, 23.1 ± 4.1. Three
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of the seven vertebral fractures occurred when boys had BMI > 25. 4. Discussion Long-term corticosteroid treatment results in glucocorticoid induced osteoporosis (GIOP). GIOP is characterized by demineralization of trabecular bone and an increased incidence of vertebral and rib fractures [27]. In contrast, cortical bone is spared with GIOP and appendicular fractures are rare [28]. Histological mechanisms that contribute to the increased fracture propensity observed with GIOP include: decreased osteoblastogenesis, increased bone marrow adiposity and a reduced lifespan of osteoblasts and osteocytes [27]. Few studies have examined longitudinal changes in bone health among boys with DMD on corticosteroids. Boys with DMD have a lower bone and muscle mass, higher fat mass and a higher incidence of fragility fractures than age matched controls [17]. This is due in part to reduced mobility, muscle mass loss, and long-term corticosteroid treatment [6,11,16]. Unlike patients with other forms of GIOP, children with DMD also have structural and functional abnormalities of their muscle. The combined effects of GIOP and DMD progression may contribute to the disruption of the muscle-bone unit and increase fragility fracture risk [12,26]. Some argue skeletal changes in boys with DMD on steroids are similar to steroid naive boys [29]. Thus, the compromised muscle-bone unit in DMD may have a greater effect on bone health than corticosteroid treatment [30]. Our findings suggest that the changes in body composition (lean, fat and bone mass) are important for bone health in DMD. Before deflazacort was started both the age-based and height-adjusted lumbar BMD Z-scores were reduced. These boys walk well but most do not run, jump, or do vigorous weight-bearing activities. Their reduced muscle strength and lower physical activity levels may compromise the bone-muscle unit and contribute to their lower BMD. After starting deflazacort, there were no significant changes in height-adjusted BMD Z-scores until ambulation was lost. There was a significant change (p < 0.05) in agebased BMD Z-scores within first two years of starting deflazacort and a consistent decline with subsequent years of therapy. The decline was most marked as the boys lost their ability to walk. Of importance, the height-adjusted BMD Z-scores were always significantly higher than the agebased Z-scores at all time intervals. Since these boys on deflazacort are all very short, and height can influence BMD Z-scores, we suggest that the height-adjusted BMD Z-scores might best reflect their bone health and identify those with low Z-scores who should consider therapy to augment bone mass. Deflazacort did not increase the risk of long-bone fractures in our study when we compare fracture rates to those of steroid naive boys with DMD. Long-bone fracture frequency (21%) and locations in this cohort are similar
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to previous published observations for both corticosteroid treated DMD boys [2,15–17] and steroid naive DMD boys [17,29]. However, boys on corticosteroids are at increased risk of vertebral fractures [8,9,13,15,16]. This increased risk may be due to GIOP and disease progression with loss of muscle and increased fat mass. Steroid naive boys likely do not experience back pain and vertebral fractures as they have limited spinal mobility following spinal surgery and hardware insertion to correct scoliosis. Ten percent of boys on corticosteroids require scoliosis surgery, a stark contrast to the 90% of boys not on corticosteroids who require scoliosis surgery [2,15]. The reported frequency (16%) of vertebral fractures in our cohort is likely an under-estimation as our standard of care was that x-rays of the spine were only done when boys experienced vertebral back pain or progressive scoliosis. Previous studies have reported a vertebral fracture frequency of 19–32% [8,13,15]. Many glucocorticoid induced vertebral fractures may be asymptomatic [28]. A consensus is evolving to suggest that symptomatic acute vertebral fractures be treated with intravenous (IV) bisphosphonates [6]. IV Pamidronate and Zoledronic acid for 12 months have been found to reduce pain symptoms associated with vertebral fractures and improve lumbar spine BMD in boys with DMD [31]. There is no consensus for the management of an asymptomatic vertebral fracture identified on a routine spine X-ray in paediatric patients. There are technical challenges to obtaining DXA scans of boys with DMD. The boys in this study had increased body fat %, which may falsely elevate BMD [32]. Height is an important variable in determining BMD in DMD due to the short stature in boys on daily deflazacort treatment and height adjustments should be made to BMD values [25,33]. Total body less head BMD DXA scans may be confounded by poor positioning in the scanner due to central obesity, frog leg positioning due to elbow, hip and knee flexion contractures as the boys age [11]. It has been suggested that the femoral neck may be a more accurate measure of BMD in DMD but it requires increased technical skill and is often not feasible to measure accurately over time as progression of hip flexion and abduction contractures preclude accurate femoral neck region of interest assignment over time [20,34]. There are limitations to our study. It is not possible to do similar studies in steroid naive boys with DMD since corticosteroids are now standard of care [1,5]. This study was not intended to compare the effects of different corticosteroids on bone health, only those of deflazacort. We did not record serial assessments on bone age and pubertal status. The boys likely all have delayed puberty contributing to low heights for their age and age-based BMD Z-scores. When these assessments are done, the bone age and pubertal status are delayed by 3–6 years. We do not order spine x-rays unless clinically indicated as this population already receives a large number of radiographs. Thus, our study does not address the question of how common are asymp-
tomatic vertebral fractures in this population. In addition, we did not follow serum and urinary bone markers as these assays were not routinely available when our study began. Furthermore, their importance in monitoring paediatric bone health and available normative ranges were not established. As most boys with DMD are now living into adulthood, maintaining bone health is important for their quality of life. Long-term, multicentre prospective studies with standardized clinical protocols are required to explore related clinical questions and develop evidence-based guidelines for bone health monitoring and treatment in DMD. Routine use of height-adjusted Z-scores is advocated for use in routine clinical practice [35]. References [1] Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, Part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9:77–93. [2] 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;16:249–55. [3] Birnkrant DJ, Bushby K, Amin RS, et al. The respiratory management of patients with Duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatr Pulmonol 2010;45:739–48. [4] McDonald CM, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases Duchenne muscular dystrophy. Am J Phys Med Rehabil 1995;74(5 (Suppl.)):S70–92. [5] Moxley RT, Pandya S, Ciafaloni E, Fox DJ, Campbell K. Change in natural history of Duchenne muscular dystrophy with long-term corticosteroid treatment: implications for management. J Child Neurol 2010;25:1116–29. [6] Bianchi ML, Biggar WD, Bushby K, Rogol AD, Rutter M, Tseng B. Endocrine aspects of Duchenne muscular dystrophy. Neuromuscul Disord 2011;21:298–303. [7] Iannitti T, Capone S, Feder D, Palmieri B. Clinical use of immunosuppressants in Duchenne muscular dystrophy. J Clin Neuromuscul Dis 2010;12:1–21. [8] King WM, Ruttencutter R, Nagaraja HN, et al. Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy. Neurology 2007;68:1607–13. [9] Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: long-term effect. Am J Phys Med Rehabil 2005;84(11):843–50. [10] LoCascio V, Ballanti P, Milani S, et al. A histomorphometric longterm longitudinal study of trabecular bone loss in glucocorticoidtreated patients: prednisone versus deflazacort. Calcif Tissue Int 1998;62:199–204. [11] Bachrach LK. Taking steps towards reducing osteoporosis in Duchenne muscular dystrophy. Neuromuscul Disord 2005;15:86–7. [12] Schoenau E, Frost HM. The “muscle-bone unit” in children and adolescents. Calcif Tissue Int 2002;70:405–7. [13] Bothwell JE, Gordon KE, Dooley JM, MacSween J, Cummings EA, Salisbury S. Vertebral fractures in boys with Duchenne muscular dystrophy. Clin Pediatr (Phila) 2003;42:353–6. [14] Henderson RC, Berglund LM, May R, et al. The relationship between fractures and DXA measures of BMD in the distal femur of children and adolescents with cerebral palsy or muscular dystrophy. J Bone Miner Res 2010;25:520–6. [15] Houde S, Filiatrault M, Fournier A, et al. Deflazacort use in Duchenne muscular dystrophy: an 8-year follow-up. Pediatr Neurol 2008;38:200–6.
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˚ hlander A-C, et al. Bone mass [26] So¨derpalm A-C, Magnusson P, A development in patients with Duchenne and Becker muscular dystrophies: a 4-year clinical follow-up. Acta Paediatr 2012;101(4): 424–32. [27] Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res 1999;14:1061–6. [28] Weinstein RS. Clinical practice: glucocorticoid-induced bone disease. N Eng J Med 2011;365:62–70. [29] Larson CM, Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. J Pediatr Orthop 2000;20:71–4. [30] Crabtree NJ, Roper H, McMurchie H, Shaw NJ. Regional changes in bone area and bone mineral content in boys with Duchenne muscular dystrophy receiving corticosteroid therapy. J Pediatr 2010;156(450– 455):e451. [31] Sbrocchi AM, Rauch F, Jacob P, Matzinger M, Ward LM. The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with Duchenne muscular dystrophy. Osteoporos Int 2012, http://dx.doi.org/10.1007/s00198-012-1911-3 [Epub ahead of print]. [32] Siminoski K, O’Keeffe M, Le´vesque J, Hanley D, Brown JP. Canadian association of radiologists technical standards for bone mineral densitometry reporting. Can Assoc Radiol J 2011;62:166–75. [33] Leonard MB, Zemel BS. Current concepts in pediatric bone disease. Pediatr Clin North Am 2002;49:143–73. [34] Harcke HT, Kecskemethy H, Conklin D, Scavina M, Mackenzie W, McKay C. Assessment of bone mineral density in Duchenne muscular dystrophy using the lateral distal femur. J Clin Neuromuscul Dis 2006;8:1–6. [35] Gordon CM, Bachrach LK, Carpenter TO, et al. Dual energy x-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD pediatric official positions. J Clin Densitom 2008;11(1):43–58.
Neuromuscular Disorders 22 (2012) 1040–1045 www.elsevier.com/locate/nmd
Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy A.L. Mayo a,⇑, B.C. Craven a,b, L.C. McAdam c,d, W.D. Biggar c,d a b
Department of Medicine, Division of Physiatry, University of Toronto, Canada Toronto Rehabilitation Institute – University Health Network, Toronto, Canada c Department of Paediatrics, University of Toronto, Canada d Holland Bloorview Kids Rehabilitation Hospital, Toronto, Canada Received 5 June 2012; accepted 29 June 2012
Abstract Quality of life in Duchenne Muscular Dystrophy (DMD) has improved significantly with corticosteroid treatment. However, corticosteroids decrease bone mass and increase vertebral fragility fracture risk. We report on bone health in 39 boys with DMD on long-term deflazacort (0.9 mg/kg/day) therapy. Bone health was defined by lumbar (L1–L4) bone mineral density (BMD), long-bone and/or symptomatic vertebral fractures. Lumbar BMD was reported as height-adjusted Z-scores at initiation of deflazacort (T0) and 1–2 year intervals thereafter. Subcapital body fat percentage and ambulatory status were recorded. At T0, 39 boys, aged 6.6 ± 1.6 years had height-adjusted BMD Z-score 0.5 ± 0.8, and 23.5 ± 5.0% body fat. Height-adjusted Z-scores remained stable with years of deflazacort until loss of ambulation and accrual of body fat. Nine long-bone fractures occurred in eight ambulating boys, two before T0. Seven vertebral fractures occurred in six non-ambulatory boys after P5 years of deflazacort with height-adjusted Z-score 1.8 ± 0.7, and 47.8 ± 12% body fat. Bone health in DMD is influenced by disease progression, corticosteroids, BMD Z-scores and fat mass accumulation. Adjustments for short stature must be considered during BMD interpretation. Percent body fat and ambulatory status are useful bone health indicators. Routine use of height adjusted Z-scores is advocated for use in routine clinical practice. Ó 2012 Elsevier B.V. All rights reserved. Keywords: Duchenne Muscular Dystrophy; Deflazacort; Bone mineral density; Fractures
1. Introduction Duchenne Muscular Dystrophy (DMD), an x-linked recessive disorder, occurs in approximately one in 3500 live male births. DMD is associated with progressive skeletal and cardiac muscle weakness. Males typically present with proximal muscle weakness at 3–6 years of age and lose ambulation by age 7–12 years (average age 10) [1,2]. Death usually occurs during the 2nd or 3rd decade due to cardiac and/or respiratory failure. Life expectancy has been increased with improved cardiorespiratory care [1,3,4].
⇑ Corresponding author. Present address: 55 Ian Drive, Keswick ON, Canada L4P 4G9. Tel.: +1 905 252 8404. E-mail address: [email protected] (A.L. Mayo).
0960-8966/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.nmd.2012.06.354
With daily corticosteroid treatment, boys ambulate 3–5 years longer, have preserved cardiac and pulmonary function and significantly reduced scoliosis [1,2,5]. Prednisone (0.75 mg/kg/day) and deflazacort, an oxazolone derivative of prednisolone (0.9 mg/kg/day) are the most frequently used corticosteroids to treat DMD [1,6]. Side effects of corticosteroids can be significant and include excessive weight gain, short stature, behavioural issues, posterior capsular cataracts, delayed puberty and reduced bone mass [2,5–9]. Deflazacort, is reported to be less detrimental to trabecular bone than prednisone [10]. Boys with DMD have at least two major risk factors for compromised bone health; a disruption of the muscle-bone unit and treatment with corticosteroids [11,12]. Fractures in corticosteroid treated DMD boys most frequently occur
A.L. Mayo et al. / Neuromuscular Disorders 22 (2012) 1040–1045
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Table 1 Changes in lumbar spine BMD Z-scores and body composition with years of deflazacort therapy among BMD boys.
Boys (N) Age (years) Height Z-score (mean ± SD) Age-based BMD Z-score (mean ± SD) Height-adjusted BMD Z-score (mean ± SD) Body fat% (mean ± SD) BMI (mean ± SD) Independent ambulation (N, %) * ** ¥
T0
Years of deflazacort therapy 1–2 (1.6 ± 0.5)
3–4 (3.4 ± 0.6)
5–6 (5.2 ± 0.5)
7–8 (7.1 ± 0.5)
39 6.6 ± 1.6 1.0 ± 1.3 1.1 ± 0.8¥ 0.5 ± 0.8 23.5 ± 5.0 16.6 ± 1.8 39/39 (100%)
36 8.0 ± 1.5 1.6 ± 0.9* 1.5 ± 1.0*,¥ 0.7 ± 0.9 27.5 ± 10.7* 18.8 ± 3.2* 36/36 (100%)
24 10.3 ± 1.5 2.1 ± 1.0* 1.8 ± 0.9¥ 0.7 ± 1.1 39.8 ± 9.6** 22.1 ± 3.6** 22/24 (96%)
25 11.8 ± 1.8 2.4 ± 1.1 2.4.±1.3 ¥ 0.9 ± 1.2 43.2 ± 11.8 22.9 ± 5.4 21/25 (88%)
13 14.2 ± 1.7 2.7 ± 0.7 3.6 ± 1.1**,¥ 1.8 ± 0.8* 51.1 ± 10.6* 23.2 ± 4.1 5/13 (38%)
p < 0.05. p < 0.001 significance between previous value and follow-up value. p < 0.001 significance between age and Ht-Z based lumbar BMD Z-score.
Table 2 Long-bone and vertebral fracture demographics and DXA results.
Number of fractures Age at fracture Height Z-score Years on deflazacort Age-based BMD Z-score Height-adjusted BMD Z-score Body fat% BMI * **
Long-bone fractures
Vertebral fractures
9 9.0 ± 3.0 1.4 ± 1.2 2.8 ± 2.1 2.3 ± 0.7 1.5 ± 0.6
7 14.1 ± 2.4* 3.2 ± 0.8* 7.5 ± 1.8** 3.5 ± 0.7* 1.8 ± 0.7
33 ± 14.2 19.7 ± 5.5
47.8 ± 12.0* 23.1 ± 4.1
p < 0.05. p < 0.001 significance between long-bone and vertebral fracture values.
in the distal femur, proximal tibia and vertebrae, all areas of high trabecular bone content [8,13,14]. In comparison with steroid-naive DMD boys, corticosteroids are reported to increase vertebral fracture risk but not long-bone fracture risk [2,7,9,15–18]. There is currently no published international consensus for the management of bone health among boys with DMD. However, recent international workshops have focused on the development of recommendations for the optimal management of bone health in boys with DMD on corticosteroids [6,19–21]. Vitamin D and calcium supplements have been shown to benefit the preservation of bone mass among DMD boys [22]. Recommendations for the use of bisphosphonate therapy to treat DMD boys with low bone mass and high fracture risk are evolving [6,21]. The primary objective of this study is to describe and compare the changes in lumbar spine (L1–L4) BMD with years of deflazacort therapy using both age-based and height-adjusted Z-scores. The secondary objectives of this study are to describe the frequency and site of fractures in a cohort of boys with DMD treated with daily deflazacort; and to explore the associations between fracture frequency, duration of deflazacort therapy, body fat composition, ambulatory status, and lumbar bone mineral density.
2. Patients and methods Clinical data were obtained prospectively from a convenience sample of 39 boys with DMD on deflazacort treatment, followed at Holland Bloorview Kids Rehabilitation Hospital’s multidisciplinary neuromuscular clinic between January 2001 and December 2011. All patients met the following diagnostic criteria for DMD: (1) onset of weakness prior to age 5, (2) male, (3) proximal muscle weakness, (4) elevated serum creatinine kinase, and (5) DMD confirmed through muscle biopsy and/or dystrophin gene analyses. All boys initiated deflazacort while still ambulatory and before experiencing significant loss of muscle function as evidenced by increased falls, difficulty with rising from supine to standing or difficulty climbing stairs. This was usually between 4 and 6 years of age. The initial dose of deflazacort was 0.9 mg/kg/day. The dose of deflazacort was adjusted with weight gain to a maximum of 39 mg/day. The mean dose at 10 years of age was 0.8 ± 0.18 mg/kg/ day, at 15 years was 0.55 ± 0.09 mg/kg/day and 18 years was 0.5 ± 0.2 mg/kg/day [2]. Supplements of elemental calcium (750 mg) and vitamin D (1000 IU) were advised. Prior to initiation of deflazacort, serum vitamin D levels were performed and if low, 2000 IU of vitamin D were recommended. BMD was routinely assessed before deflazacort was started (T0) and every 1–2 years thereafter. Patient monitoring was done every 4 months using a standard clinical protocol [2]. Boys were independently evaluated by a clinic nurse, physiotherapist, occupational therapist, respiratory therapist, and physician at each visit. Clinic visits included documentation of height, weight, ambulatory status, fractures, and adherence to calcium and vitamin D supplements. Height for ambulatory boys was measured to the nearest 0.1 centimetre using a stadiometer. Height for non-ambulatory boys was calculated based on their measured ulnar length from the tip of the ulnar styloid to the olecranon [23]. BMI was calculated as weight/height2 (kg/m2). Loss of ambulation was defined as the inability to walk 10 m independently on a level floor without gait aids.
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Only symptomatic vertebral fractures were recorded. Symptoms included a history of back pain when changing position, localized back pain when driving over minor bumps in their power wheelchair, or riding on the school bus, and localized pain on palpation over the vertebral body and spinous process. Spine X-rays were only ordered for boys reporting vertebral back pain or progressive scoliosis noted on physical examination. Spine X-rays were performed at Holland Bloorview by the same qualified X-ray technician. The X-rays were reviewed by the same radiologist using the semi-quantitative method as described by Genant et al. [24]. Vertebrae were graded on visual inspection as normal (grade 0), mildly deformed with 20–25% reduction of anterior, middle and/or posterior height (grade 1), moderately deformed with 25–40% reduction of height (grade 2) or severely deformed with approximately 40% reduction in height in any height and area. A vertebral body was diagnosed as fracture if graded 1 or higher. Vertebral fractures were classified as wedge, biconcave and/or crush deformity based on the atlas by Genant et al. [24]. Bone mineral density (BMD) testing was performed at Toronto Rehabilitation Institute using a Hologic QDR 4500W (Waltham, MA, USA) densitometer. The change in Z-scores with years of deflazacort treatment was evaluated from baseline (T0) and subsequently over serial scans. Scans of the whole body and lumbar (L1–L4) regions were acquired in array mode and analyzed based on the manufacturers’ guidelines for pediatric total body less head and lumbar spine assessment using the Hologic AP spine software, version 12.3, respectively. Lumbar BMD (g/cm2) and body fat% from total body less head DXA scans were recorded. The coefficients of variation for the scanner were within acceptable limits as defined by the manufacturer. All DXA scans were done using the same densitometer and by one of two ISCD certified DXA technologists. Lumbar BMD results were compared to an updated 2011 reference curve for age, sex and ethnicity matched healthy boys to obtain the age-based Z-score (SD units above or below the mean) [25]. Due to the boys short stature and smaller bone volumes, their DXA scans were also analyzed adjusting for both age and height [22,26] The height Z-score (Ht-Z) for the boys’ chronological age was calculated using the Epi Info Nutrition Calculator provided free online by the US Centres for Disease and Prevention website (http://www.cdc.gov/epiiinfo). This Ht-Z score was then used in the equations described by Zemel et al. to calculate a height-adjusted BMD Z-score [25]. Descriptive statistics (mean and SD) were performed on the BMD age-based and height-adjusted Z-scores and body fat at deflazacort initiation (T0) and then with years of therapy. A Student’s t-test was performed on the agebased and height-adjusted lumbar Z-scores for statistically significant differences between these mean values. Fracture site was reported as long-bone (upper or lower extremity) and vertebral. Demographic and BMD values
for boys with and without fractures were analyzed with descriptive statistics (mean ± SD, Student’s t-test) for associations between fractures and age, duration of deflazacort treatment, ambulatory status, body fat% and BMI. Ethics approval was obtained through Holland Bloorview Kids Rehabilitation Hospital. The clinical data presented herein were obtained prospectively via chart abstraction from Holland Bloorview Kids Rehabilitation Hospital’s clinical DMD database, with participant/parent consent/assent as appropriate for participation. 3. Results The 39 boys were 6.6 ± 1.6 years old and all independently ambulating when deflazacort was started (T0). At the end of the follow-up period (December 2011), there were 38 boys aged 12.8 ± 3.6 years old with 6.6 ± 2.8 years of deflazacort treatment (range 1.4–11.0 years). Twentyeight of the 38 boys were still ambulating independently. When the boys were older than 12 years, puberty was delayed by three or more years. One of the 39 boys died during the follow-up period of suspected fat embolism syndrome at age 14 following a minor fall. During the year of his death, he was non-ambulatory with height-adjusted lumbar BMD Z-score of 2.8, age-based lumbar Z-score of 4.6, body fat of 58.6% and BMI 27.3. The changes in lumbar spine BMD over time are expressed both as the age-based and the height-adjusted Z-scores and are summarized in Table 1. The boys entered the study at different ages and times during the study period, so the denominator for the number of scans and years on deflazacort varies across time points. We have reported the denominator for each time period. At T0, 39 of 39 of the boys were aged 6.6 ± 1.6 years with a height Z-score of 1.0 ± 1.3 SD below age matched boys. Their T0 age-based lumbar BMD Z-score was 1.1 ± 0.8 and height-adjusted BMD Z-score was 0.5 ± 0.8. Thirty-six of the 39 boys, aged 8.0 ± 1.5 years had scans after 1.6 ± 0.5 years of deflazacort. They were of shorter stature with height Z-score 1.6 ± 0.9 vs 1.0 ± 1.3 at T0 (p < 0.05). Their age-based BMD Z-score had significantly decreased to 1.5 ± 1.0 (p < 0.05). In contrast, the heightadjusted BMD Z-score was not significantly decreased at 0.7 ± 0.9. Twenty-four of the 39 boys, aged 10.3 ± 1.5 years had scans after 3.4 ± 0.6 years of deflazacort. They were significantly shorter height Z-score of 2.1 ± 1.0 vs 1.6 ± 0.9 (p < 0.05). Their age-based BMD Z-score had decreased to 1.8 ± 0.9 and height-adjusted BMD Z-score was unchanged ( 0.7 ± 1.1). Twenty-five of the 39 boys, aged 11.8 ± 1.8 years had scans after 5.2 ± 0.5 years of deflazacort. Their height Zscore had further decreased to 2.4 ± 1.1. Their age-based BMD Z-score further decreased to 2.4 ± 1.3 and heightadjusted BMD Z-score was slightly decreased, at 0.9 ± 1.2.
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Thirteen of the 39 boys, aged 14.2 ± 1.7 years had scans after 7.1 ± 0.5 years of deflazacort. Their height Z-score was low, 2.7 ± 0.7. Their age-based BMD Z-score was significantly decreased, 3.6 ± 1.1 (p < 0.001) as was the height-adjusted BMD Z-score of 1.8 ± 0.8 (p < 0.05). At T0 and for all time points, the age-based BMD Z-score was significantly decreased (p < 0.001) than the height-adjusted BMD Z-score. Independent ambulation was preserved for the majority of the boys, 21 of 25 (88%) with more than 5 but less than 7 years of therapy. Of the boys with over 7 years of therapy, only five of 13 (38%) were independent ambulators (A). The eight boys that were non-ambulatory had significantly lower (p < 0.05) age-based BMD Z-score of 4.2 ± 0.6 than the five ambulatory boys age-based Z-score of 3.0 ± 1.0. The height-adjusted BMD Z-score of the non-ambulatory boys, 2.2 ± 0.6 was clinically lower than the ambulating boys height-adjusted Z-score of 1.2 ± 0.9 but did not reach statistical significance (p = 0.07). The eight nonambulating boys had slightly but not significantly higher (p = 0.26) body fat percentage of 55.5 ± 2.8 to five ambulatory boys with a body fat 47.6 ± 14.5%. During the study period, there were nine long-bone fragility fractures in eight of the 39 boys (21%); three upper extremity and six lower extremity fractures. Two boys had an upper extremity fracture before T0, and one of these boys subsequently had a lower extremity fracture while on deflazacort. All long-bone fractures occurred in independently ambulating boys. Three of the six boys (50%) lost independent ambulation at ages 10, 11 and 15 years old when they had a leg fracture. Six boys complained of vertebral back pain and had vertebral fractures confirmed on spine X-ray. One boy had a single lumbar vertebral fracture; all other boys had three or more vertebral fractures in the lower thoracic and upper lumbar regions. All vertebral fractures occurred in nonambulatory boys. Two of the six boys had a long-bone fracture prior to their vertebral fracture. The vertebral fractures were all anterior wedge and biconcave fractures with no radiculopathy or change in spinal alignment. DXA scan data at time of fracture for the long-bone and vertebral fractures are summarized in Table 2. Long-bone fractures occurred in younger boys mean age 9.0 ± 3.0 years, falling while independently ambulating and after 2.8 ± 2.1 years of deflazacort therapy. Vertebral fractures occurred in older, non-ambulatory boys, age 14.1 ± 2.4 years. All boys with vertebral fractures had over 5 years of deflazacort. The age-based BMD Z-scores for the boys with vertebral fractures were significantly lower (p < 0.05) than boys with long-bone fractures. All vertebral fractures occurred at an age-based BMD Z-score of 6 2.5 and at height-adjusted BMD Z-score 1.8 ± 0.7. The vertebral fractures occurred at significantly higher (p < 0.05) body fat percentage, 47.8 ± 12% than the long-bone fractures, 33 ± 14.2%. Five of the seven vertebral fractures occurred in boys with P50% body fat. BMI was on average, normal at time of vertebral fracture, 23.1 ± 4.1. Three
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of the seven vertebral fractures occurred when boys had BMI > 25. 4. Discussion Long-term corticosteroid treatment results in glucocorticoid induced osteoporosis (GIOP). GIOP is characterized by demineralization of trabecular bone and an increased incidence of vertebral and rib fractures [27]. In contrast, cortical bone is spared with GIOP and appendicular fractures are rare [28]. Histological mechanisms that contribute to the increased fracture propensity observed with GIOP include: decreased osteoblastogenesis, increased bone marrow adiposity and a reduced lifespan of osteoblasts and osteocytes [27]. Few studies have examined longitudinal changes in bone health among boys with DMD on corticosteroids. Boys with DMD have a lower bone and muscle mass, higher fat mass and a higher incidence of fragility fractures than age matched controls [17]. This is due in part to reduced mobility, muscle mass loss, and long-term corticosteroid treatment [6,11,16]. Unlike patients with other forms of GIOP, children with DMD also have structural and functional abnormalities of their muscle. The combined effects of GIOP and DMD progression may contribute to the disruption of the muscle-bone unit and increase fragility fracture risk [12,26]. Some argue skeletal changes in boys with DMD on steroids are similar to steroid naive boys [29]. Thus, the compromised muscle-bone unit in DMD may have a greater effect on bone health than corticosteroid treatment [30]. Our findings suggest that the changes in body composition (lean, fat and bone mass) are important for bone health in DMD. Before deflazacort was started both the age-based and height-adjusted lumbar BMD Z-scores were reduced. These boys walk well but most do not run, jump, or do vigorous weight-bearing activities. Their reduced muscle strength and lower physical activity levels may compromise the bone-muscle unit and contribute to their lower BMD. After starting deflazacort, there were no significant changes in height-adjusted BMD Z-scores until ambulation was lost. There was a significant change (p < 0.05) in agebased BMD Z-scores within first two years of starting deflazacort and a consistent decline with subsequent years of therapy. The decline was most marked as the boys lost their ability to walk. Of importance, the height-adjusted BMD Z-scores were always significantly higher than the agebased Z-scores at all time intervals. Since these boys on deflazacort are all very short, and height can influence BMD Z-scores, we suggest that the height-adjusted BMD Z-scores might best reflect their bone health and identify those with low Z-scores who should consider therapy to augment bone mass. Deflazacort did not increase the risk of long-bone fractures in our study when we compare fracture rates to those of steroid naive boys with DMD. Long-bone fracture frequency (21%) and locations in this cohort are similar
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to previous published observations for both corticosteroid treated DMD boys [2,15–17] and steroid naive DMD boys [17,29]. However, boys on corticosteroids are at increased risk of vertebral fractures [8,9,13,15,16]. This increased risk may be due to GIOP and disease progression with loss of muscle and increased fat mass. Steroid naive boys likely do not experience back pain and vertebral fractures as they have limited spinal mobility following spinal surgery and hardware insertion to correct scoliosis. Ten percent of boys on corticosteroids require scoliosis surgery, a stark contrast to the 90% of boys not on corticosteroids who require scoliosis surgery [2,15]. The reported frequency (16%) of vertebral fractures in our cohort is likely an under-estimation as our standard of care was that x-rays of the spine were only done when boys experienced vertebral back pain or progressive scoliosis. Previous studies have reported a vertebral fracture frequency of 19–32% [8,13,15]. Many glucocorticoid induced vertebral fractures may be asymptomatic [28]. A consensus is evolving to suggest that symptomatic acute vertebral fractures be treated with intravenous (IV) bisphosphonates [6]. IV Pamidronate and Zoledronic acid for 12 months have been found to reduce pain symptoms associated with vertebral fractures and improve lumbar spine BMD in boys with DMD [31]. There is no consensus for the management of an asymptomatic vertebral fracture identified on a routine spine X-ray in paediatric patients. There are technical challenges to obtaining DXA scans of boys with DMD. The boys in this study had increased body fat %, which may falsely elevate BMD [32]. Height is an important variable in determining BMD in DMD due to the short stature in boys on daily deflazacort treatment and height adjustments should be made to BMD values [25,33]. Total body less head BMD DXA scans may be confounded by poor positioning in the scanner due to central obesity, frog leg positioning due to elbow, hip and knee flexion contractures as the boys age [11]. It has been suggested that the femoral neck may be a more accurate measure of BMD in DMD but it requires increased technical skill and is often not feasible to measure accurately over time as progression of hip flexion and abduction contractures preclude accurate femoral neck region of interest assignment over time [20,34]. There are limitations to our study. It is not possible to do similar studies in steroid naive boys with DMD since corticosteroids are now standard of care [1,5]. This study was not intended to compare the effects of different corticosteroids on bone health, only those of deflazacort. We did not record serial assessments on bone age and pubertal status. The boys likely all have delayed puberty contributing to low heights for their age and age-based BMD Z-scores. When these assessments are done, the bone age and pubertal status are delayed by 3–6 years. We do not order spine x-rays unless clinically indicated as this population already receives a large number of radiographs. Thus, our study does not address the question of how common are asymp-
tomatic vertebral fractures in this population. In addition, we did not follow serum and urinary bone markers as these assays were not routinely available when our study began. Furthermore, their importance in monitoring paediatric bone health and available normative ranges were not established. As most boys with DMD are now living into adulthood, maintaining bone health is important for their quality of life. Long-term, multicentre prospective studies with standardized clinical protocols are required to explore related clinical questions and develop evidence-based guidelines for bone health monitoring and treatment in DMD. Routine use of height-adjusted Z-scores is advocated for use in routine clinical practice [35]. References [1] Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, Part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9:77–93. [2] 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;16:249–55. [3] Birnkrant DJ, Bushby K, Amin RS, et al. The respiratory management of patients with Duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatr Pulmonol 2010;45:739–48. [4] McDonald CM, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases Duchenne muscular dystrophy. Am J Phys Med Rehabil 1995;74(5 (Suppl.)):S70–92. [5] Moxley RT, Pandya S, Ciafaloni E, Fox DJ, Campbell K. Change in natural history of Duchenne muscular dystrophy with long-term corticosteroid treatment: implications for management. J Child Neurol 2010;25:1116–29. [6] Bianchi ML, Biggar WD, Bushby K, Rogol AD, Rutter M, Tseng B. Endocrine aspects of Duchenne muscular dystrophy. Neuromuscul Disord 2011;21:298–303. [7] Iannitti T, Capone S, Feder D, Palmieri B. Clinical use of immunosuppressants in Duchenne muscular dystrophy. J Clin Neuromuscul Dis 2010;12:1–21. [8] King WM, Ruttencutter R, Nagaraja HN, et al. Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy. Neurology 2007;68:1607–13. [9] Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: long-term effect. Am J Phys Med Rehabil 2005;84(11):843–50. [10] LoCascio V, Ballanti P, Milani S, et al. A histomorphometric longterm longitudinal study of trabecular bone loss in glucocorticoidtreated patients: prednisone versus deflazacort. Calcif Tissue Int 1998;62:199–204. [11] Bachrach LK. Taking steps towards reducing osteoporosis in Duchenne muscular dystrophy. Neuromuscul Disord 2005;15:86–7. [12] Schoenau E, Frost HM. The “muscle-bone unit” in children and adolescents. Calcif Tissue Int 2002;70:405–7. [13] Bothwell JE, Gordon KE, Dooley JM, MacSween J, Cummings EA, Salisbury S. Vertebral fractures in boys with Duchenne muscular dystrophy. Clin Pediatr (Phila) 2003;42:353–6. [14] Henderson RC, Berglund LM, May R, et al. The relationship between fractures and DXA measures of BMD in the distal femur of children and adolescents with cerebral palsy or muscular dystrophy. J Bone Miner Res 2010;25:520–6. [15] Houde S, Filiatrault M, Fournier A, et al. Deflazacort use in Duchenne muscular dystrophy: an 8-year follow-up. Pediatr Neurol 2008;38:200–6.
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