Use Of Bisphosphonates In Children Research Articles

Bone alterations of pamidronate therapy in children with cerebral palsy complicating orthopedic management.

Cerebral palsy (CP) is a heterogeneous group of disorders with different clinical types and underlying genetic variants. Children with CP are at risk for fragility fractures secondary to low bone mineral density, and although bisphosphonates are prescribed for the treatment of children with bone fragility, there is limited information on long-term bone impact and safety. Children with CP usually present overtubulated bones, and the thickening of cortical bone by pamidronate treatment can potentially further narrow the medullary canal. Our purpose was to report bone alterations attributable to pamidronate therapy that impact orthopedic care in children with CP. The study consisted of 41 children with CP treated with pamidronate for low bone mineral density from 2006 to 2020. Six children presented unique bone deformities and unusual radiologic features attributed to pamidronate treatment, which affected their orthopedic care. The cases included narrowing of the medullary canal and sclerotic bone, atypical femoral fracture, and heterotopic ossification. Treatment with bisphosphonate reduced the number of fractures from 101 in the pretreatment period to seven in the post-treatment period ( P < 0.001). In conclusion, children with CP treated with bisphosphonate have a reduction in low-energy fractures; however, some fractures still happen, and pamidronate treatment can lead to bone alterations including medullary canal narrowing with sclerotic bone and atypical femoral fractures. In very young children, failure to remodel may lead to thin, large femoral shafts with cystic medullary canals. More widespread use of bisphosphonates in children with CP may make these bone alterations more frequent. Level of evidence: Level IV: Case series with post-test outcomes.

Legg–Calvé–Perthes disease presenting with osteoarthritis: Mechanisms of the development and prospects of conservative therapy using bisphosphonates

BACKGROUND: Aseptic necrosis of the femoral head in children remains a subject of great interest among specialists, despite its long history of study. The LeggCalvPerthes disease is the most common form of aseptic necrosis of the femoral head in children. The necrotic lesion in the femoral head results from the blockage of the arterial blood supply to the epiphysis, leading to its infarction. Some children experience a more aggressive disease course, with signs of osteoarthritis, which can result in the early development of coxarthrosis. Numerous publications have demonstrated the successful use of bisphosphonates in adult patients with aseptic necrosis of the femoral head.&#x0D; AIM: To generalize data on the use of bisphosphonates in children with the LeggCalvPerthes disease presenting with signs of osteoarthritis through the analysis of contemporary global literature.&#x0D; MATERIALS AND METHODS: A literature search was conducted in the open databases of PubMed, Science Direct, and Google Scholar, and the analysis depth spanned 20 years. The search terms used included LeggCalvPerthes disease, aseptic (avascular) necrosis of the femoral head, and bisphosphonates. The review encompassed the literature on bisphosphonates, their biological action, effectiveness of their use in patients with aseptic necrosis of the femoral head, and results of our research.&#x0D; RESULTS: Studies on the efficacy of bisphosphonates in children with LeggCalvPerthes disease are limited. Currently, the effect of bisphosphonates on disease course and outcome is unknown. Despite this, mechanisms of chronic inflammation are increasingly mentioned in the literature, which may directly or indirectly influence the clinical course and outcome of the disease. The key is the hyperactivity of osteoclasts in osteonecrosis. The experience of using bisphosphonates in adult patients with aseptic necrosis of the femoral head had positive results in preventing the progression of the deformity of femoral head deformity.&#x0D; CONCLUSIONS: Bisphosphonates are specific inhibitors of osteoclast activity, which has been used in many diseases. The results and inferences of using bisphosphonates in children with LeggCalvPerthes disease will lead to the formulation of a new treatment algorithm.

Trends of use of bisphosphonates in children with secondary osteoporosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The use of bisphosphonates in children: review of the literature and guidelines for dental management

Bisphosphonates are inhibitors of osteoclastic bone resorption with therapeutic benefit in a variety of bone disorders in both adults and children. While these agents have been routinely used in adults for the past three decades, their more recent introduction into paediatric medicine means there is a paucity of data on long-term safety and effects on dental development. There is uncertainty regarding the dental management of children treated with bisphosphonates, particularly when invasive dental procedures, such as extractions and oral surgical procedures, are required. There are limited data with which to make recommendations about the dental management of patients treated with bisphosphonates, and there are no published recommendations that specifically address paediatric patients. This paper aims to outline paediatric uses and adverse effects of bisphosphonates and present recommendations on the dental management of children receiving bisphosphonates.

Bisphosphonate use in children with pediatric osteoporosis and other bone conditions.

Bisphosphonates (BPs) are used most commonly in children with osteogenesis imperfecta, resulting in increased trabeculae and cortical thickness, increased bone density as measured by DXA (Dual Energy X-ray Absorptiometry), and improved vertebral morphology. Less well documented in controlled trials are decrease in long bone fractures, improved strength and motor function, and decreased pain. Outside of children with osteogenesis imperfecta, use of bisphosphonates in children is increasing, all of which is off-label. This is seen in children with other chronic conditions resulting in pediatric osteoporosis and insufficiency fractures. Additional indications include steroid dependency with progressive loss of bone density, avascular necrosis of bone, and chronic regional pain syndrome. This review highlights the potential benefits and risks of the use of bisphosphonates in these unique children at risk for fracture or bone collapse.

Bisphosphonate therapy in children

Bisphosphonates are analogues of pyrophosphates that bind to bone and inhibit osteoclast resorption of bone and promote osteoclast apoptosis. They are used widely in adults for treatment of metastatic bone disease and osteoporosis. The off-label use of bisphosphonates in children is expanding to treat low bone mass and osteoporotic disorders like osteogenesis imperfecta and cerebral palsy-related osteopenia, as well as localized bone disorders like fibrous dysplasia. The effects of these drugs on the growing skeleton are still incompletely understood, and they should be used with care. Overall, when administered with close monitoring, they have been shown to be beneficial in treating a number of childhood low bone mass states and bone diseases. Bisphosphonates also offer particular promise in treating Legg-Calve-Perthes disease and avascular necrosis of the hip in young people.

Can bisphosphonates play a role in the treatment of children with chronic kidney disease?

In patients with chronic kidney disease (CKD) renal osteodystrophy, in the form of either low- or high-turnover bone disease, is quite common. While renal transplantation is expected to reverse renal osteodystrophy, long-term treatment with glucocorticoids before and/or after transplantation may lead to osteoporosis instead. Osteoporosis is defined as a skeletal disease with low bone mineral density, microarchitectural deterioration, and concomitant fragility. In adults, bisphosphonates are widely used to treat osteoporosis and other diseases associated with excessive bone resorption. In pediatric CKD patients the efficacy and safety of these drugs have not yet been addressed adequately and thus no evidence-based recommendations regarding the optimal type of bisphosphonate, dosage, or duration of therapy are available. Furthermore, while in adults the determination of areal bone mineral density is sufficient to diagnose osteoporosis, this is not the case in children. Instead, in pediatric patients, careful morphological assessment of bone structure and formation is required. Indeed, data from studies with uremic rats indicated that bisphosphonates, via a deceleration of bone turnover, have the potential not only to aggravate pre-existing adynamic bone disease, but also to impair longitudinal growth. Thus, the widespread use of bisphosphonates in children with CKD should be discouraged until the risks and benefits have been carefully elucidated in clinical trials.

Approach to the Child with Fractures

Evaluation of the child with fractures is challenging, as no clear guidelines exist to distinguish traumatic from pathological fractures. Although most fractures in childhood are benign, recurrent fractures may be associated with a wide variety of primary skeletal diseases as well as secondary causes, necessitating a careful history and physical exam to guide the evaluation. There is no "gold standard" for the evaluation and treatment of children with fractures and low bone mineral density (BMD); therefore, the diagnosis of osteoporosis in a pediatric patient should be made using a combination of clinical and radiographic features. Interpretation of bone densitometry in growing patients presents a unique set of challenges because areal BMD measured by dual-energy x-ray absorptiometry depends on multiple dynamic variables. Interpretation of pediatric dual-energy x-ray absorptiometry should be based on Z-scores (sd scores compared to age, sex, and ethnicity-matched controls), using normative databases specific to the brand of densitometer and the patient population. Given the skeleton's ability to recover from low BMD through modeling and remodeling, optimizing management of underlying conditions leading to bone fragility is the initial step. Conservative measures including calcium and vitamin D supplementation and weight-bearing physical activity are important interventions that should not be overlooked. The use of bisphosphonates in children and adolescents is controversial due to lack of long-term efficacy and safety data and should be limited to clinical trials and compassionate therapy in children with significantly compromised quality of life. Close monitoring is required, and further study is necessary to assess their long-term safety and efficacy in children.

Use of bisphosphonates in children—proceed with caution

A clinical review of studies on bisphosphonate therapy for pediatric osteoporosis has revealed that they increase BMD, but whether they also improve fracture rates or functions of daily life is unclear. Can the findings of this clinical review help inform clinicians whether, when and how to use these agents in children?

Clinical Review: Bisphosphonate Use in Childhood Osteoporosis

As awareness of osteoporosis in childhood has increased, so have pressures to consider use of the pharmacological agents used to treat osteoporosis in adults. This review examines available research on the efficacy and safety of bisphosphonate therapy for pediatric osteoporosis. We reviewed the medical literature for key articles and consensus statements on the use of bisphosphonates in children through June 2008. We compared reports using varying bisphosphonate agents, doses, and duration of therapy to treat osteogenesis imperfecta and a variety of secondary causes of osteoporosis in children. Conclusions drawn from a recently published Cochrane analysis and the consensus statements from experts in the field were considered as well. Use of bisphosphonate therapy in pediatric patients remains controversial because of inadequate long-term efficacy and safety data. For this reason, many experts recommend limiting use of these agents to those children with recurrent extremity fractures, symptomatic vertebral collapse, and reduced bone mass. Current data are inadequate to support the use of bisphosphonates in children to treat reductions in bone mass/density alone. More research is needed to define appropriate indications for bisphosphonate therapy and the optimal agent, dose, and duration of use in pediatric patients.

A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management

To review outcome measures and treatment costs in children with juvenile idiopathic arthritis (JIA) and low bone mineral density (BMD) and/or fragility fractures. To review evidence for effectiveness and safety of bisphosphonates and calcium and/or vitamin D in these children. To assess long-term bone health in adults with JIA. Major databases were searched up to July 2005 for effectiveness studies and up to January 2005 for costs. A structured search strategy was conducted. For the evaluation of long-term bone health, outcome data were derived from two cohorts of adult patients with JIA. As there were few published cost data, an ongoing UK longitudinal study (CAPS) provided background data on the cost of managing JIA. Sixteen studies (78 children with JIA) were included. At baseline, the children had BMD below the expected values for age- and sex-matched children; treatment with bisphosphonates increased BMD with mean percentage increases in spine BMD varying from 4.5 to 19.1%. None of the studies with control groups compared results between the intervention and control groups, they only compared each group with its own baseline. Overall, studies were heterogeneous in design, of variable quality and with no consistency in methods of assessing and reporting outcomes. Hence, data could not be combined or an effect size calculated. A further 43 papers were included in the safety review; side-effects were generally transient. Two studies assessed treatment with calcium and/or vitamin D; BMD was increased from 0.75 to 0.830 g/cm2 after 6 months and BMD Z-score from -2.8 to -2.3 after 6 months and -2.4 after 1 year. There are relatively few long-term studies on the occurrence of low BMD and fragility fractures in children with JIA, with most studies only following children for 1 or 2 years. However, the long- and short-term data indicate that children with JIA have a lower BMD and more fractures than children without JIA. There are very few data on long-term bone health from adults who have JIA, but studies indicate that low BMD persists into adulthood, although adults in remission from JIA may attain the same BMD as healthy adults. From the available data, any predictors of low BMD and fractures in children and adults with JIA remain uncertain. No studies were found that discussed the costs of treating children with JIA and low BMD and/or fragility fractures. In CAPS, 297 of 457 children with JIA attended a 12-month follow-up visit. The mean annual total cost per child in the first year after diagnosis was 1649 pounds (standard deviation 1093 pounds, range 401-6967 pounds). The highest cost component was appointments with paediatric rheumatologists. The study is continuing to accrue and follow up patients and further analyses will be undertaken as the study progresses. BMD, adjusted for size, should be assessed as the primary outcome in studies of bone health in children with JIA. Quantitative computed tomography could be used where equipment is available as it offers the advantage of measuring volumetric density. Bisphosphonates are a promising treatment for osteoporosis in children with JIA, but the quality of the current evidence is poor. The accurate assessment of outcome is crucial. There are still uncertainties about the use of bisphosphonates in children, including whether the positive effects of treatment continue over time, the length of treatment and the maximal bone mass gain that can be achieved. Adults with JIA may have persistent low BMD compared with an otherwise healthy population together with an increased risk of fracture. There are no studies evaluating the costs of treating children with JIA and low BMD and/or fragility fractures. There are few data evaluating the costs of treating JIA in general. In the first 12 months after diagnosis, children with all JIA disease subtypes consume large, but highly variable, quantities of health service resources, the largest component being the consultant rheumatology appointments. Data from a larger cohort, over a longer period, are required to substantiate these results further. Further research is needed to assess more clearly the role and permit licensing of bisphosphonates for treatment of children, and in particular, longer-term studies.

Osteoporosis in Children and Adolescents

Bone mass increases progressively during childhood, but mainly during adolescence when approximately 40% of total bone mass is accumulated. Peak bone mass is reached in late adolescence, and is a well recognised risk factor for osteoporosis later in life. Thus, increasing peak bone mass can prevent osteoporosis. The critical interpretation of bone mass measurements is a crucial factor for the diagnosis of osteopenia/osteoporosis in children and adolescents. To date, there are insufficient data to formally define osteopenia/osteoporosis in this patient group, and the guidelines used for adult patients are not applicable. In males and females aged <20 years the terminology 'low bone density for chronologic age' may be used if the Z-score is less than -2. For children and adolescents, this terminology is more appropriate than osteopenia/osteoporosis. Moreover, the T-score should not be used in children and adolescents. Many disorders, by various mechanisms, may affect the acquisition of bone mass during childhood and adolescence. Indeed, the number of disorders that have been identified as affecting bone mass in this age group is increasing as a consequence of the wide use of bone mass measurements. The increased survival of children and adolescents with chronic diseases or malignancies, as well as the use of some treatment regimens has resulted in an increase in the incidence of reduced bone mass in this age group. Experience in treating the various disorders associated with osteoporosis in childhood is limited at present. The first approach to osteoporosis management in children and adolescents should be aimed at treating the underlying disease. The use of bisphosphonates in children and adolescents with osteoporosis is increasing and their positive effect in improving bone mineral density is encouraging. Osteoporosis prevention is a key factor and it should begin in childhood. Pediatricians should have a fundamental role in the prevention of osteoporosis, suggesting strategies to achieve an optimal peak bone mass.

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