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Bone health in children with neuromuscular disorders: current opinions and future directions “There is certainly a need for future studies to assess the risk:benefit ratio,
safety and efficacy of initiating bisphosphonate treatment for the prevention of fractures in severely affected patients...” Over the past decade, there have been many advances in the diagnosis and management of pediatric osteoporosis. The novel use of bisphosphonates for children with severe osteogenesis imperfecta has provided significant improvement in bone density and patients’ quality of life in terms of reducing fracture rate, bone pain and improving mobility [1] . Bisphosphonate treatment has now also expanded to different types of pediatric bone diseases, such as fibrous dysplasia and osteoporosis secondary to systemic diseases. The reported outcomes with these interventions has been very positive. Children with spastic quadriplegia associated with cerebral palsy (CP), or other neuro muscular disorders (NMD) resulting in impaired ambulation, such as muscular dystrophy, spinal muscular atrophy and myelodysplasia, are prone to profound low bone mass (osteopenia) and low impact fractures. Collectively, this group comprises by far the largest number of children with significant osteopenia or osteoporosis at our pediatric institution and we suspect that this observation will hold true at most pediatric referral centers. Many complex questions continue to challenge us. The first question that most clinicians ask is when to order bone mineral density (BMD) testing in these children. Unlike cystic fibrosis or survivors of childhood cancer, in which there have been published guidelines for the timing of initial dual-energy x‑ray absorptiometry (DXA), there has been no consensus on when to order such noninvasive tests in nonambulatory children and adolescents. Based on a study of 117 children and adolescents with moderate and severe CP by Henderson et al., virtually almost all (97%) children more than 9 years of age who were unable to stand, had significant osteopenia [2] . Fractures occurred in 26% of children older than 10 years and increased in prevalence with increasing age [3] . Based on these statistics, it is
reasonable to obtain DXA early in nonambulatory children and adolescents, especially in those with risk factors such as poor nutrition, anticonvulsant or corticosteroid use, and a severe degree of neurological impairment. Clinicians should be aware that the Z score provided by most DXA machine manufactures compares BMD with age- and gender-matched normal references. Children with CP or NMD who typically have impaired growth and low bodyweight, and resultant smaller bone size, are more likely to have lower Z scores when compared with age- and gender-matched normal children. The Z score that is adjusted by height, bone age or bodyweight is more appropriate since it helps avoid over-diagnosis of low bone density. In our institution, the lumbar BMD Z score is adjusted by bodyweight and Tanner stage based on the normative data reported by Southard et al., which studied 218 healthy children, aged 1–19 years [4] . The results of multiple regression analyses in this study demonstrated that Tanner stage and weight were the best predictive indicators of bone mass and BMD [4] . Alternatively, Henderson and colleagues have demonstrated that the distal femur may be a more reliable site of DXA measurements in these children [5] – it is the most common site of fracture and is not interfered by the metal ware from orthopedic surgery in the spine or hip that many patients may have. Many issues remain uncertain regarding the use of bisphosphonate therapy in children with low bone density associated with CP or NMD: who to treat, when to treat, what preparation (oral or intravenous bisphosphonates) and how long should bisphosphonate treatment be provided? For those patients with clinical bone fragility, we believe that bisphosphonate therapy should be offered, as there have been multiple reports of benefits of intravenous pamidronate in increasing BMD Z scores and decreasing fracture rate in these children [6–8] . The dosage used is based
10.2217/PHE.10.49 © 2010 Future Medicine Ltd
Pediatric Health (2010) 4(5), 463–465
Sasigarn A Bowden
Author for correspondence: Department of Pediatrics, The Ohio State University College of Medicine, Nationwide Childrens’ Hospital, Columbus, OH, USA
[email protected]
John D Mahan
Department of Pediatrics, The Ohio State University College of Medicine, Nationwide Childrens’ Hospital, Columbus, OH, USA
Keywords • bisphosphonate • BMD • neuromuscular disorder • osteoporosis • pamidronate
ISSN 1745-5111
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editorial – Bowden & Mahan on the procotol first developed for children with osteogenesis imperfecta [1] , which is 1 mg/kg/day for 3 days, repeated every 3 months for 1 year. The published studies reported 1 year of therapy with increased BMD for the duration of the study, with a limited number of patients followed after discontinuation of therapy. Plotkin et al. reported the efficacy of lower doses of pamidronate given at the dosage of 0.75 mg/kg/day for 2 days every 16 weeks for 1 year [9] . This study included children with severe CP (no ambulation) and low BMD of the femoral neck below three standard deviations as inclusion criteria. Most patients in this study received pamidronate treatment for low BMD without history of prior fracture, with the intention to prevent fractures in children with low BMD.
“Many issues remain uncertain regarding the use of bisphosphonate therapy in children with low bone density associated with CP or NMD: who to treat, when to treat, what preparation and how long...” These positive outcomes continue to generate debate among clinicians in the field. The question is whether we should wait until a child with profound disabilities and osteopenia, with extremely low BMD below four or five standard deviations goes through the pain and consequences of a fracture before initiating treatment, or should we start the treatment to prevent fractures (with low-dose pamidronate like the study by Plotkin et al. [9] or oral bisphosphonates). One could justify the treatment for prevention of fractures if the treatment is safe and effective. The long-term consequences of bisphosphonate treatment in this population are, of course, not available to us at this time. Our own experience with children treated for 3–5 years with bisphosphonates has revealed no significant complications, although inconvenience and costs are a concern. Oral risedronate, a third-generation bisphosphonate, has been reported to increase BMD in children with CP and this approach may prove more reasonable in terms of initiating treatment at the early stages of diminished bone mass [10] . It is important to make sure that other measures are optimized in the prevention or treatment of osteoporosis. These include optimizing nutritional status, especially calcium and vitamin D intake, and physical therapy. Interventions to improve vitamin D status are required for 464
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virtually all of these individuals, and must not be neglected in light of their risk for poor bone health. A recent study showed improvement in lumbar spine BMD of 6% in children with CP receiving the weight-bearing physical activity program, but no change was seen in tibial BMD [11] . Another study reported the effects of low-frequency oscillation mechanical stimulation for 6 months in children with disabilities: improving BMD in the tibia by 6%, with no improvement in BMD in the lumbar spine [12] . The nonpharmacologic methods of incorporating physical activity and therapy appears promising; however, minimal increases in the percent change in BMD have been noted with these interventions, compared with up to 40% improvement in BMD with bisphosphonate therapy. The primary outcome was BMD measurement in these and other studies; whether this translates to fracture prevention warrants further exploration. It has been established in adults that bisphosphonates are effective as a prevention of osteoporosis in adults with postmenopausal osteoporosis or steroid-induced osteoporosis. There is certainly a need for future studies to assess the risk:benefit ratio, safety and efficacy of initiating bisphosphonate treatment for the prevention of fractures in severely affected patients (children and adults) with significantly diminished bone mass associated with neurological impairment. Such studies will require a large number of patients and long-term follow-up of important biologic outcomes, such as fractures, in addition to proximate outcomes, such as BMD. Newer bisphosphonate treatment options, such as singledose intravenous zoledronic acid, or other longacting oral bisphosphonates, such as ibandronate, will also require further study to prove effectiveness and establish a role in this population of children and adults.
“It is important to make sure that other measures are optimized in the prevention or treatment of osteoporosis.” Given that the single most costly medical problem in a residential facility for severely disabled children is the treatment of fracture, the outcomes also need to focus on cost–effectiveness. The cost for inpatient and outpatient care for a femoral fracture in a single patient can be as high as US$10,000–30,000, providing further rationale to continue this journey to find answers to these important questions, for this special population. future science group
Bone health in children with neuromuscular disorders –
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
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