Bone mineral density and bone metabolism in Duchenne muscular dystrophy

Very few studies on bone mineral density and bone metabolism in Duchenne muscular dystrophy (DMD) have been reported. DMD is a severe, progressive muscular disease resulting in death at a young age. No specific therapies are available, but corticosteroids induce improvement and slower progression of the disease. However, long-term steroid therapy is a serious risk factor for osteoporosis. This study was aimed at evaluating bone mineral density and calciotropic hormones in a group of children affected by DMD, with or without steroid therapy. Bone mineral density was measured by DXA scan on lumbar spine and total body. Evaluation of calcium, phosphorus, bone turnover markers and calciotropic hormones was performed. Thirty-two children affected by DMD were studied: twenty-two on long-term prednisone therapy, ten not taking corticosteroids. Bone mineral density was lower than normal for age in all patients, and even lower in the group of steroid-treated children. Trunk and lower limb bone mineral densities were more reduced than upper limb mineral density, especially in the steroid-treated subjects. A marked reduction in spine bone mineral density, hypocalciuria, low 25-hydroxyvitamin D levels, and increased bone turnover markers were observed, and even these especially in the steroid-treated group. In conclusion, decreased bone mineral density and derangement of calcium metabolism were present in DMD patients, and were worsening during corticosteroid therapy. It is thus recommended that bone and mineral metabolism be carefully evaluated in patients with DMD, so that appropriate measures could be taken, especially now that chronic corticosteroid therapy is frequently given.     

Duchenne muscular dystrophy

Duchenne muscular dystrophy is an X-linked disease of muscle caused by an absence of the protein dystrophin. Affected boys begin manifesting signs of disease early in life, cease walking at the beginning of the second decade, and usually die by age 20 years. Until treatment of the basic genetic defect is available, medical, surgical, and rehabilitative approaches can be used to maintain patient function and comfort. Corticosteroids, including prednisone and a related compound, deflazacort, have recently been shown to markedly delay the loss of muscle strength and function in boys with Duchenne muscular dystrophy. Surgical release of lower extremity contractures may benefit some patients. Approximately 90% of boys with Duchenne muscular dystrophy will develop severe scoliosis, which is not amenable to control by nonsurgical means such as bracing or adaptive seating. The most effective treatment for severe scoliosis is prevention by intervening with early spinal fusion utilizing segmental instrumentation as soon as curves are ascertained and before the onset of severe pulmonary or cardiac dysfunction.     

Duchenne muscular dystrophy

Opinion statement Duchenne muscular dystrophy (DMD) is not treatable; there is no cure. More than a decade ago, randomized trials demonstrated that oral steroid therapy was of benefit to DMD patients by prolonging ambulation. Although few significant side effects were reported, study patients were followed for 18 months or less. However, when treating DMD with steroids, the clinician must consider beginning treatment in mid-childhood and continuing until adolescence or longer, a total of at least 10 years. There is no evidence that steroids are associated with prolonged life or with improved pulmonary or cardiac function in DMD. It is clear that the risk of side effects increases with duration of use of oral steroids. Therefore, oral steroids are not recommended for treatment of DMD on a routine basis. If, in certain cases, one does institute therapy, the patient should be monitored carefully for side effects, maintain dietary restriction, and exercise regularly.     

The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with Duchenne muscular dystrophy

Summary

The impact of intravenous bisphosphonate treatment to treat painful vertebral fractures in boys with DMD has not been documented. In this retrospective observational study of seven boys, 2?years of intravenous bisphosphonate therapy was associated with back pain improvement and stabilization or increases in the height ratios of fractured vertebrae.

Introduction

Boys with Duchenne muscular dystrophy (DMD) are at risk for vertebral fractures. We studied the impact of intravenous bisphosphonate therapy for the treatment of painful vertebral fractures in DMD.

Methods

This was a retrospective observational study in seven boys with DMD (median 11.6?years, range 8.5 to 14.3) treated with intravenous pamidronate (9?mg/kg/year) or zoledronic acid (0.1?mg/kg/year) for painful vertebral fractures.

Results

At baseline, 27 vertebral fractures were evident in the seven boys. After 2?years of bisphosphonate therapy, 17 of the fractures had an increase in the most severely affected vertebral height ratio, 10 vertebrae stabilized, and none showed a decrease in height ratio. Back pain resolved completely (N?=?3) or improved (N?=?4). The median change in lumbar spine volumetric bone mineral density Z-score was 0.5 standard deviations (interquartile range, ?0.3 to 1.7). Two boys had three incident vertebral fractures in previously normal vertebral bodies that developed over the observation period. There was a decline in the trabecular bone formation rate on trans-iliac bone biopsy but no evidence of osteomalacia. First-dose side effects included fever and malaise (N?=?4), hypocalcemia (N?=?2), and vomiting (N?=?1); there were no side effects with subsequent infusions.

Conclusions

Intravenous bisphosphonate therapy was associated with improvements in back pain and stabilization to improvement in vertebral height ratios of previously fractured vertebral bodies. At the same time, such therapy does not appear to completely prevent the development of new vertebral fractures in this context.     

Scoliosis associated with Duchenne muscular dystrophy

The pathoanatomy and natural history of scoliosis associated with Duchenne muscular dystrophy were established by a review of 105 patients. Scoliosis developed in 95% of these patients after the loss of ambulation. The direction of the curve was determined by asymmetrical contracture of the iliotibial band. Functional classification using the radiographic sitting kyphotic index proved a reliable guide to the age at loss of ambulation and life expectancy, as well as the rate of progression and eventual severity of spinal deformities. Spinal orthoses failed to control curve progression in 94% of patients (30 of 32). Fourteen patients underwent spinal fusion with excellent long-term results.     

Mivacurium in children with Duchenne muscular dystrophy

The authors retrospectively reviewed their experience with mivacurium for neuromuscular blockade in seven children with Duchenne muscular dystrophy. Mivacurium was administered to seven children ranging in age from 8.3 to 14.4 years and in weight from 29 kg to 68 kg during either posterior spinal fusion or lower extremity release. An initial bolus dose of 0.2 mg·kg^?1 was followed by a continuous infusion. Neuromuscular blockade was monitored with a standard twitch monitor and the TOF (2 Hz for 2 s). Complete suppression of all four twitches occurred in 1.5 to 2.6 min. The continuous infusion was started with the return of the first twitch and adjusted to maintain one twitch. Time to recovery of the first twitch varied from 12 to 18 min. Continuous infusion requirements varied from 3 to 20 μg·kg^?1 with an average for the case of less than 10 μg·kg^?1 min^?1 in five of the seven patients. A moderate increase in sensitivity to mivacurium in this patient population is suggested by a decrease in infusion requirements and a prolonged effect following the initial dose.     

Lung function in Duchenne muscular dystrophy

Summary Over 90% of patients with Duchenne muscular dystrophy develop a scoliosis when they become wheelchair bound. The scoliosis is progressive and is associated with deteriorating lung function. The purpose of this study was firstly to assess whether a standing regimen, in patients who had gone off their feet, protected against the development of scoliosis and affected their lung function, and secondly to evaluate the effect of spinal stabilisation in patients who had developed a progressive scoliosis. The results of the first part of this study showed that a standing regimen significantly delayed the progression of scoliosis and that patients who complied with the standing regimen had a significantly better lung function, as measured by vital capacity and peak expiratory flow rate, than those patients who did not stand. Spinal stabilisation prevented deterioration in the scoliosis, whereas the deformity continued to progress relentlessly in patients who did not undergo surgery. The patients who underwent spinal stabilisation maintained a significantly better lung function and had an improved survival compared with the patients who refused surgery.Paper read at the ESDS meeting, Birmingham 1994, and selected for full publication.     

Bone mineral density correlation with fractures in nonambulatory pediatric patients

Although bone mineral density (BMD) as related to T score (comparison with young adult) is well correlated with fracture risk in adults, no such correlation has been confirmed in children. Quadriparetic children have lower BMD than age-matched controls, as well as a higher rate of fragility fracture. This study examines a cohort of children with quadriparesis and other nonambulatory children to correlate BMD with fragility fractures.We hypothesize that fracture in these children is related to BMD as correlated with patient size and that age comparison (Z-score) is less important.Review of all children with a dual-energy x-ray absorptiometry scan from August 2003 to June 2005 identified 101 nonambulatory pediatric patients (excluding children with osteogenesis imperfecta or metabolic bone disease). Sixteen patients had insufficient data, leaving 85 patients, 26 of whom had experienced fragility fractures. Lateral femoral dual-energy x-ray absorptiometry scan was performed on one or both legs, then regions were averaged. Data was evaluated for statistical correlation between BMD and body size as evidenced by body mass index (BMI). Other factors, including age, Z-score, and height and weight independently were secondarily evaluated for correlation with fracture risk.Correlation was demonstrated between history of fracture and BMD when related to BMI (P = 0.002).In conclusion, in these nonambulatory children, the combination of the BMD of the distal femur and BMI correlates well with occurrence of fragility fracture and may relate to fracture risk. This relationship is independent of the child's chronological age and Z-score. This information may be helpful prognostically to define a treatment algorithm for low bone density on a case-by-case basis.     

Duchenne muscular dystrophy with associated growth hormone deficiency

A patient with Duchenne muscular dystrophy (DMD) and growth hormone (GH) deficiency is described who had no clinical evidence of muscular weakness before initiation of GH replacement therapy. Treatment with human GH resulted in appearance of symptoms of easy fatigability and proximal muscle weakness. Thorough investigations including serum creatinine phosphokinase (CK) levels is recommended in every patient with GH deficiency before starting GH replacement therapy.     

Scoliosis correction with pedicle screws in Duchenne muscular dystrophy

This report describes the spinal fixation with pedicle-screw-alone constructs for the posterior correction of scoliosis in patients suffering from Duchene muscular dystrophy (DMD). Twenty consecutive patients were prospectively followed up for an average of 5.2 years (min 2 years). All patients were instrumented from T3/T4 to the pelvis. Pelvic fixation was done with iliac screws similar to Galveston technique. The combination of L5 pedicle screws and iliac screws provided a stable caudal foundation. An average of 16 pedicle screws was used per patient. The mean total blood loss was 3.7 l, stay at the intensive care unit was 77 h and hospital stay was 19 days. Rigid stabilisation allowed immediate mobilisation of the patient in the wheel chair. Cobb angle improved 77% from 44° to 10°, pelvic tilt improved 65% from 14° to 3°. Lumbar lordosis improved significantly from 20° to 49°, thoracic kyphosis remained unchanged. No problems related to iliac fixation, no pseudarthrosis or implant failures were observed. The average percentage of predicted forced vital capacity (%FVC) of the patients was 55% (22–94%) preoperatively and decreased to 44% at the last follow-up. There were no pulmonary complications. One patient with a known cardiomyopathy died intraoperatively due to a sudden cardiac arrest. The rigid primary stability with pedicle screws allowed early mobilisation of the patients, which helped to avoid pulmonary complications.     

北京郊区12?14岁男女学生骨密度的研究

目的　了解本市郊区 1 2～ 1 4岁少年男女骨密度 (BMD)的变化规律。方法　利用双能X射线骨密度仪对 30 6例健康男女中学生行左前臂、腰椎和全身扫描 ,按性别不同 ,每 1岁分 1个组。结果　该年龄段男女孩各部位BMD每年都有不同程度的增加 ,女孩高于男孩。各部位BMD以腰椎最高 ,全身总的BMD次之 ,前臂BMD最低。 1 2～ 1 3岁女孩身高与各部位BMD呈明显正相关 (P <0 0 1 ,r=0 331～ 0 62 1 ) ,1 3～ 1 4岁男孩身高与各部位BMD呈明显正相关 (P <0 0 1 ,r =0 339～0 662 )。体重与BMD始终相关 ,腰椎与全身总的BMD相关性最后 (P <0 0 0 1 ,r =0 674～ 0 81 1 )。结论　不同部位BMD的增长快慢不一 ,测量腰椎BMD能够较好地反映全身BMD状况 ,体重对BMD的影响比身高对BMD的影响大     

Treatment options for Duchenne muscular dystrophy

Opinion statement The main goal in the treatment of Duchenne muscular dystrophy (DMD) is to maintain ambulation for as long as possible and to anticipate and manage the associated complications, such as joint contractures, scoliosis, cardiomyopathy, respiratory insufficiency, and weight gain. Cognitive and behavioral symptoms occur in about one third of patients, and it is important to recognize and manage them promptly, developing an individualized plan at school and at home to maximize the patient’s cognitive abilities. In the late phase of the disease, palliative care is of paramount importance. Corticosteroid therapy (prednisone and deflazacort) is the only effective pharmacologic treatment for DMD. Daily prednisone treatment increases muscle strength and function, improves pulmonary function, and significantly slows the progression of weakness. Deflazacort has a similar effect on muscle strength, but it is not available in the United States. Treatment with corticosteroid should be offered to all patients with DMD, but the beneficial effects and potential adverse effects should be fully discussed before treatment begins. The optimal dose of prednisone is 0.75 mg/kg per day, up to a maximum of 40 mg/d. If adverse effects occur, a decrease in dosage is appropriate. Monitoring of muscle function and adverse effects by a neurologist or neuromuscular specialist is strongly recommended. Physical and occupational therapists should be involved early in the treatment of patients with DMD to develop a program that includes heel cord stretching and exercise. In the later phases, these therapists can recommend adaptive equipment and maximize independence. Orthopedic consultation is important in monitoring and managing scoliosis and joint contractures in the nonambulatory phase of the disease. Pulmonary evaluation for ventilatory care is important; pulmonary consultation is essential when vital capacity declines. The use of assistive cough devices, nasal bilevel positive airway pressure, and tracheostomy must be discussed with patients and their families. For all patients with DMD, particularly those receiving prednisone, consultation with a dietitian is very helpful to control weight and maintain a healthy diet.     

Obstructive apnoeas in Duchenne muscular dystrophy.

BACKGROUND--In order to clarify the treatment of sleep hypoxaemias in Duchenne muscular dystrophy polysomnographic studies were performed on patients at home with the purpose of recruiting them into two clinical therapeutic trials. Observations concerning the nature of sleep hypoxaemia in these patients are presented. METHODS--Twenty one non-ambulant patients with Duchenne muscular dystrophy aged 13-23 years with no symptoms of sleep hypoventilation or apnoea were studied for two consecutive nights with eight channel polysomnography. A comparative study was performed in 12 age matched normal male subjects. The evolution of sleep hypoxaemia with age was studied in 14 patients with Duchenne muscular dystrophy. RESULTS--Thirteen of the 21 patients had hypoxaemia below 90% during sleep, and 12 of the 13 had discrete hypoxaemic dips in association with apnoeas; 60% of all apnoeas were obstructive in nature. The hypoxaemic periods became more frequent with increasing age and, in two patients at three year follow up, were more frequently associated with central or possibly "pseudocentral" apnoeas. Although the normal subjects had a few apnoeic episodes, none had sleep hypoxaemia below 90% saturation. CONCLUSION--The sleep related breathing abnormality in Duchenne muscular dystrophy is initially obstructive and this has implications for management.