Abstract
Although for many decades bisphosphonates were used for adult bone loss, bisphosphonate administration in pediatric patients is new and was initiated in the past 15-year. The indications for pediatric bisphosphonates was extended to childhood malignancies with bone involvement, after additional effects were unveiled for bisphosphonates with recent research. In this article we review childhood bone loss and conditions with bone involvement in which bisphosphonate therapy have been used. We also review mechanisms of action of bisphosphonates, and present indications of bisphosphonate therapy in pediatric patients based on results of clinical trials.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
The use of bisphosphonate therapy in pediatric patients was suggested in 1998 when the cyclic administration of intravenous pamidronate in children with osteogenesis imperfecta resulted in reduction in bone resorption, increase in bone density, and reduction in fracture incidence [1]. Since the mechanism of action in children is different from adults, as bone in children is a growing tissue and responds to bisphosphonates differently than the adult bone, it is difficult to extrapolate the adult bisphosphonate therapy regimens to the pediatric patients. Two years after discontinuation of pamidronate therapy, older teens with osteogenesis imperfecta maintained their spine bone mass, while the bone mass declined in younger teens. The persistence of gains in BMD after bisphosphonate therapy appeared to be dependent on the age of the children and the amount of regional residual bone growth [2]. In 2007 and 2014 a Cochrane Database Systemic Review [3]–[5] concluded there were insufficient data to support the use of bisphosphonates as standard therapy in children. Importantly, although many clinical trials in pediatric patients reported significant gains in BMD and decrease in pain compared to placebo with bisphosphonates, they did not conclude that bisphosphonates significantly reduce the incidence of fractures in osteogenesis imperfecta [4], neither bisphosphonates improve survival of cancer patients. However, safety and efficacy of short-term therapy (≤2-yr) is sufficient to justify their use in severe cases of bone loss such as osteogenesis imperfecta and pediatric bone malignancies associated with fracture and pain.
Molecular mechanisms of actions of bisphosphonates
The molecular mechanisms of action of bisphosphonates were described recently. All bisphosphonates are characterized by 2 phosphonate groups sharing a common carbon atom (P-C-P) backbone, responsible for the strong affinity of bisphosphonates for bone mineral, the hydroxyapatite. The adsorption of bisphosphonate molecule to bone mineral is responsible for the uptake and retention of bisphosphonate on the skeleton, its diffusion and storage within the bone, and its potential release from bone [6].
The simple bisphosphonates attached to calcium are taken up by osteoclasts by endocytosis and are incorporated as toxic, non-hydrolysable metabolites, methylene-containing ATP analogues. Methylene-containing metabolites, or ATP analogues, contain the P-C-P groups of bisphosphonates in place of the pyrophosphate (P-O-P) moiety of ATP. ATP analogs are resistant to hydrolytic breakdown and the release of phosphate [7]. Metabolites of simple bisphosphonates closely resemble proton pump inhibitors (PPi), and as such, can be incorporated into the active site of aminoacyl-tRNA synthetase enzyme in the cell. These cytotoxic metabolites condensate and accumulate in the cytosol of osteoclasts and cause apoptosis of these cells. No other cell type can acidify the bone surface, a condition required for this adsorption [8]–[10]. It was recently found that monocytes and macrophages also were able to internalize bisphosphonates, but only transiently. On the contrary, RANKL and TNF alpha can prevent the bisphosphonates apoptosis and restore osteoclast’s bone resorption activities [9],[10]. In summary, simple bisphosphonates act as pro-drugs, absorbed by osteoclasts where they accumulate as toxic metabolites and cause apoptosis of osteoclasts and prevent the bone resorption.
Nitrogen-containing bisphosphonates (N-bisphosphonates) are up to several magnitude more potent than simple bisphosphonates and they inhibit osteoclasts using a different pathway [11]. N-bisphosphonates inhibit enzymes of cholesterol synthesis, the mevalonate enzyme pathway and the farnesyl diphosphate synthase, within osteoclasts. The inhibition of these enzymes prevents the prenylation of small GTPases and causes unprenylated GTPases. Accumulation of unprenylated GTPases modifies important functions in osteoclasts including membrane trafficking and ruffling, and induces apoptosis of these cells [12]. Zoledronic acid is the most potent inhibitor of farnesyl diphosphate synthase and has the highest affinity for hydroxyapatite and the longest duration of action [13]. The inhibition of bone resorption by N-bisphosphonates is not associated with signs of cell toxicity or decrease in OC numbers at therapeutic doses. Instead, N-bisphosphonates can lead to the formation of “giant” hyper-nucleated OC associated with resorption lacunae, seen as functionally inactive pre-apoptotic osteoclasts [14],[15]. Bisphosphonates indirectly oppose key mediators of osteoclast function and survival, RANK/ RANKL, by increasing osteoprotegerin (OPG) production. Increase in OPG opposes the binding of RANKL to the RANK receptor [16]–[19]. In addition to anti-osteoclastic effects, bisphosphonates have antitumor properties. In pre-clinical trials in neuroblastoma, it is shown that zoledronic acid stimulates tumor-specific T cells by enhancing the anti-tumor activity of natural-killer cells [20]. In clinical trials, zoledronic acid combined with conventional chemotherapy, decreases the production of IL6, which is associated with poor-outcome of neuroblastomas [21]. Despite a decrease in bone remodeling, bone formation parameters are maintained because osteoblasts remain active, resulting in a positive remodeling balance [22].
Effects of bisphosphonates on pediatric patients
In children with osteogenesis imperfecta, the most studied cause of pediatric bone loss, intravenous pamidronate therapy increases the size of vertebral bones and reshapes pre-existing vertebral compression fractures. Older children with lower bone density gains more in BMD than younger, although younger children have less deficit in BMD at base [23]. Two years after discontinuation of intravenous pamidronate, areal BMC Z-scores in osteogenesis imperfecta children remains above pretreatment levels but below normal levels [24]. Trans-iliac histophotometry after 2 years intravenous pamidronate therapy shows maximal increases in cortical and cancellous bone thicknesses, with considerable increases in trabecular number [25]. The cortical width of iliac bone almost doubles during the first 2 years of pamidronate therapy, but changes little when therapy is continued for another 2-year. These results suggest stored bisphosphonates maintain their biological activity at least 2 years after discontinuation.
Although in adults, bisphosphonates appear to suppress bone resorption up to 10 years after discontinuation, in younger children because of higher bone turnover, recovery of recycled bisphosphonates from bone is shorter. Children with osteogenesis imperfecta treated with bisphosphonates at early age have normal or improved growth and new bone acquisition is reported in studies on long bone fractures after discontinuation of pamidronate therapy. Bisphosphonates at usual therapeutic doses do not permanently apparently disable the bone turnover mechanisms, neither usual therapeutic doses result in osteopetrosis. Overall, pamidronate therapy decreases bone remodeling, however bone formation parameters are less inhibited than bone resorption parameters, resulting in a positive remodeling balance [22]. Urinary NTX excretion decreases significantly with bisphosphonates and increases slightly after discontinuation above normal healthy levels, but it remains well below pretreatment levels [23]. Neither radiological changes in bone density nor urinary NTX are correlated with changes in BMD [25].
The improvement of BMD with only one infusion of zoledronic acid every 6 months for 1 year, and 3 monthly infusion for 12 months, were similar in pediatric spinal cord injury [26]. Also, one single infusion of zoledronic acid in adult patients reduces >30% the rate of clinical fractures over 3 years of follow up, compared with placebo [27]. These important observations, points to the possibility of shorter safer length of therapy, longer dose interval with sustained effects, and a better acceptance by patients.
The safe upper limit dose for each entity of bisphosphonate is not yet established [3]. A 2014 Cochrane Systemic Review assessed the effectiveness and safety of bisphosphonate therapy. Effect on fracture reduction was inconsistent and was observed in only two trials with statistically significant difference between oral or intravenous bisphosphonates compared to placebo control. All trials reported statistically significant increase in lumbar spine BMD Z-scores. The outcome between zoledronic acid and intravenous pamidronate were not different. Neither oral nor intravenous bisphosphonates improved significantly bone pain, growth, and functional activity versus placebo. Because of the limited number of controlled clinical trials and small number of pediatric patients the Systemic Review did not confirm that bisphosphonates decrease consistently fracture rate, nor they consistently improve pain or the functional mobility [5].
Adverse effects of bisphosphonates in pediatric patients
Bisphosphonates are generally well tolerated in pediatric patients. Adverse effects are limited, and are predictable based on previous trials. In most cases “acute phase reaction” is observed with fever, malaise, abdominal pain, vomiting, muscle or bone pain with the initiation of either intravenous or oral agents within 1–3 days, and lasting few days [1],[28]. Asymptomatic hypophosphatemia, and hypomagnesaemia and hypocalcemia causing tetany are rare and prevented with supplementation with calcium and vitamin D [29].
More serious side effects seen in adults including uveitis, thrombocytopenia, esophageal or oral ulcerations, are rare in children. One case of uveitis was reported among 19 children with Langerhans cell histiocytosis treated with bisphosphonates in a retrospective study in Japan [30]. Avascular necrosis of the jaw seen in adult [31] is not seen in pediatric patients. Severe case of respiratory distress syndrome was reported with initiation of pamidronate in an infant with history of airway disorders [32]. Osteomalacia was seen in an adolescent with fibrous dysplasia after intravenous cyclic pamidronate therapy [22].
Long term retention of high-affinity bisphosphonates is the major concern in young girls [33]–[35]. In experimental studies, bisphosphonates readily crossed the placenta. Thus bisphosphonates can possibly affect fetuses and cause hypocalcemia. Skeletal anomalies in offspring is seen in animal models [36]. A pregnancy test is recommended before therapy in teenage young women. However, full extent of fetal risks is still unknown in humans because of small number of fetuses exposed. In two infants delivered to mothers treated with bisphosphonates, asymptomatic hypocalcemia without any skeletal anomaly was reported in the newborn [35].
The greatest concern in the young patients is long term suppression of bone turnover. Osteopetrosis and pathological fractures were developed in a 12 year child treated for idiopathic hyperphosphatemia, treated with high doses of pamidronate for 33 months (up to 100 mg intravenously every three weeks) [37]. Transient and dose-dependent inhibitory effects on bone length and growth were also observed in mice after zoledronic acid therapy [38]. In a phase I trial of zoledronic acid combined with cyclophosphamide in neuroblastomas, two cases of osteosclerosis out of 21 children were reported [21].
Pediatric bone disorders: candidates for bisphosphonate therapy
The major indication for bisphosphonates in pediatric patients is osteoporosis either primary or secondary. Additional antitumor properties of bisphosphonates have recently added a second indication for bisphosphonates as adjuvant medication with chemotherapy in pediatric bone malignances.
Definition of childhood osteoporosis: Fractures with minor trauma in apparently healthy children might be a complication of unrecognized disorders with bone loss [39]. One out of 3 otherwise healthy children fractures by age 17 [40]–[42]. The 2013 revised position of International Society for Clinical Densitometry (ISCD) defines osteoporosis in children by two criteria 1) the presence of a significant fracture history indicated by either one or more vertebral compression (crush) fractures in the absence of local disease or trauma or, two or more long-bone fractures by age 10 or, three or more long-bone fractures at any age up to age 19; and 2) a low bone mineral content and areal bone mineral density (aBMD) with BMC/BMD Z-score ≤ −2.0 SD [43] [http://www.iscd.org] 2013 Pediatric Official Positions]. However aBMD Z-score ≥ −2.0 SD does not exclude osteoporosis in high risk patients since long bone or vertebral compression fractures might occur with low impact trauma. The posterior-anterior (PA) spine densitometry and a “total body less head” (TBLH) are the preferred skeletal sites for BMC and aBMD measurements. ISCD has recommended that the time interval between 2 DXA be not less than 6 months.
Primary pediatric osteoporosis result from intrinsic skeleton abnormalities, such as heritable disorders. The most common cause of primary pediatric osteoporosis is osteogenesis imperfecta, an inherited disorder characterized with bone fragility and low bone mass with an incidence of 1/10,000 births, caused by mutations of two genes that encode collagen type I alpha chain, COL1A1 and COL1A2 genes [44]. There is a wide variety of clinical severity and phonotypes, associated with a wider variety in genetic characteristics [45]. The four initial clinical types of osteogenesis imperfecta as described by Sillence [46],[47] are type I with no bone deformity, type II lethal in perinatal period, type III the most severe form in children surviving the neonatal period, with extremely short stature and short limbs, multiple spinal fractures and secondary deformities, and type IV with less severe bone deformities and variable short stature. Three additional types were later described with the same phenotypes as the first four types but with mutations not related to collagen genes and are types V, VI, and VII [48]–[51].
Bruck Syndrome and Ehlers-Danlos syndrome are rare heterogeneous autosomal recessive disorders phenotypically similar to osteogenesis imperfecta characterized by bone fragility. The genetic mechanism however consists of posttranslational modifications of collagen COL3A1 gene that result in an aberrant cross-linking of bone collagen due to under-hydroxylation [52]–[55].
Marfan syndrome, an autosomal dominant heritable disorder, results from mutations in the FBN1 gene, which encodes fibrillin-1, an extracellular matrix component found in micro-fibril structures characterized by wide variety of skeletal, ocular, and cardiovascular anomalies [56],[57]. Osteoporosis-pseudoglioma syndrome is a recessive autosomal genetic disorder involved with primary severe childhood osteoporosis and visual disturbances. Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected [58].
Secondary childhood osteoporosis result from divers processes outside of the skeleton. They comprise neuromuscular disorders associated with immobilization such as cerebral palsy, Duchenne muscular dystrophy (DMD), and spinal cord injury. DMD is an X-linked disorder arising from mutations in the dystrophin gene, which encodes a structural muscle fiber protein. In DMD association of severe muscle weakness, impaired motility, might result in high incidence of vertebral compression fractures sometime aggravated with corticoid therapy [59],[60].
Chronic illnesses such as eating disorders, liver failure, and coeliac disease, chronic inflammatory conditions including inflammatory bowel disease, systemic lupus erythematosus, HIV, renal failure, and severe burns also cause bone loss.
Secondary amenorrhea are also associated with secondary osteoporosis and include functional hypothalamic amenorrhea characterized by the dysfunction of the hypothalamic-pituitary-ovarian axis, absence of functional or anatomical lesion, associated often with stress, weight loss, or excessive exercise [61],[62]. In this syndrome, suppression of gonadotropin-releasing factor (GnRF) pulsatility, over-activity of hypothalamic-pituitary-adrenal axis, increased secretion of corticotropin-releasing hormone, disturbance of the hypothalamic-pituitary-thyroid axis [63], and estrogen deficiency [62] are present. The “female athlete triad” refers to amenorrhea, osteoporosis, and poor nutritional behavior, seen in exercise-induced amenorrhea [64],[65]. Eating disorders are 10 times more common in females and result in secondary amenorrhea in girls and low testosterone in boys. Osteopenia, osteoporosis, shorter stature, and high rates of stress fracture characterize anorexia nervosa [66],[67]. Other endocrine and reproductive disorders with hypogonadism and secondary osteoporosis include Turner syndrome, growth hormone deficiency, hyperthyroidism, diabetes, hyper-prolactinemia, and glucocorticoids excess (Cushing syndrome). Causes of iatrogenic osteoporosis include osteoporosis associated with glucocorticoid [68],[69], methotrexate, cyclosporine, radiotherapy, GnRH agonists, T4 suppressive therapy and finally, anticonvulsants therapy. Thalassemia, a hereditary anemia resulting from defects in hemoglobin synthesis, is among the most common genetic disorders with a worldwide incidence of 4.4 per 10,000 birth [70],[71]. The incidence of osteopenia or osteoporosis is estimated from 60 to 90% starting in early age, with significant decrease in OPG/RANKL ratio [72] and imbalance between bone formation and bone resorption [73],[74]. Inborn errors of metabolism associated with bone loss and osteoporosis include glycogen storage diseases, galactosemia, Gaucher disease, and homocystinuria.
Langerhans cell histiocytosis is a chronic proliferative disease characterized by uncontrolled clonal proliferation of CD1a + dendritic Langerhans cells, mostly proliferating in bone tissue [30].
Pediatric malignancies with bone involvement result in significant pain and increased morbidity and mortality [75]. The key mediator of osteoclasts survival, RANKL [16]–[19] is secreted by both osteoclasts and by malignant cells and promotes the bone resorption [76].
Neuroblastoma, the most frequent extra-cranial tumor in children has a bone metastasis rate of 56% that is generally present at diagnosis, increasing the morbidity and mortality [19]. High peripheral blood level of IL6 is associated with poor-outcome of neuroblastoma, and is believed to stimulate the invasion of osteoblastoma tumor cells to bone microenvironment. IL6 levels decrease with zoledronic acid combined with cyclophosphamide in pediatric patients with neuroblastoma [20],[21].
Ewing’s sarcoma, the second most frequent bone malignancy behind osteosarcoma in pediatric and adolescent patients, in 85% of cases, is defined by a chromosomal translocation of t(11;22)(q24;q12) [17]. Osteosarcoma, if localized at diagnostic, and when treated, has a 5-year overall survival rate of 70%, that drops to < 15% in patients with multifocal disease or relapse [17].
Initial and supportive therapy of pediatric bone disorders
Management of the primary disorders generally improves childhood osteoporosis. Weight control in eating disorders, early management of amenorrhea in anorexia nervosa [67], physical therapy in children with restricted mobility [77], correction of hemoglobin levels by transfusion and prevention of iron overload in thalassemia with iron chelating [71],[78], are the initial steps. Adequate daily intake of calcium and vitamin D are necessary. In osteogenesis imperfecta, lower serum 25OH-D levels are associated with both lower LS-aBMD Z-scores and with higher urinary bone turnover indexes (urinary NTX/Cr). Every 1 nmol/liter increase in 25OH-D increases the Z-score by 0.008. The current conservative consensus is to maintain serum 25OH-D levels above 50 nmol/liter (20 ng/ml) [79]. The 25OH-D levels are also inversely associated with PTH concentrations [80]. Recombinant hPTH therapy, the most effective anabolic agent in management of adult osteoporosis, has caused osteosarcomas in growing animal models and its use in children is not acceptable [81].
Genetic regulations of RANK/RANKL [82] and osteoprotegerin (OPG) [83] or stimulation of production of OPG that decreases RANKL/OPG ratio [16]–[18], has been considered in metastatic bone cancers. The administration of sex steroids in anorexia nervosa does not increase the BMD in adults [84] and it is not recommended in children.
Selected pediatric conditions treated with bisphosphonates
We have summarized major recent clinical trials, which studied bisphosphonate therapy in pediatric patients, in Table 1. Major pediatric conditions treated with bisphosphonates are discussed below:
Osteogenesis imperfecta
In an uncontrolled observational study in children with severe osteogenesis imperfecta, intravenous pamidronate 6.8 ± 1.1 mg/kg/year was administered up to 5 years. There was a mean annual increase in BMD of 42 ± 29%, with increase in Z-score increment of about 2 points. There was also improvement of mobility, and the fracture rate decreased compared to the rate before therapy [1].
A clinical trial analyzed bone densitometry of boys and girls aged 2 weeks to 17 with osteogenesis imperfecta types I, III, and IV, who received a 4-year intravenous pamidronate compared to “untreated” age- and type-matched controls. Patients with ages < 2 years received 0.25 mg/kg day 1, and 0.5 mg/kg days 2 and 3 every 8 weeks. Ages 2–3 years received 0.38 and 0.75 mg/kg day 1 and days 2–3 respectively, every 12 weeks. Those ages >3 years received 0.5 and 1 mg/kg/day, day1 and days 2–3 respectively, every 16 weeks. Total yearly doses in the 3 groups were the same. Results concluded that spine aBMD Z-scores, BMC, bone volume, and volumetric BMD significantly increased with intravenous pamidronate compared to control untreated children (p < 0.001 for each). The treatment was associated with both increased cortical thickness and increased trabecular compartment evidenced by both radiological and histophotometric analyses. Results suggested the most severely affected patients at the baseline were the older children and they were the ones who benefited more from intravenous pamidronate therapy [23]. Changes in serum alkaline phosphatase and urinary NTX did not correlate with gains in bone mineral density. The type of collagen mutations had no influence on results of the study [22]. Also transiliac histophotometry indicated that cancellous bone volume and cortical width initially increased significantly but changed little after year 2 of therapy [25]. To compare the effectiveness of intravenous versus oral bisphosphonate therapy, a 2-year oral alendronate therapy was also used in prospective, randomized, double-blind placebo-controlled, multicenter trials in boys and girls aged between 4 and 18 with osteogenesis imperfecta. Oral alendronate was given at 5 mg/d and 10 mg/d doses in children < 40 kg and >40 kg respectively, for 2 years. Oral alendronate significantly increased lumbar spine BMD Z-scores mostly in the first year, and suppressed sharply urinary bone resorption index, the urinary NTX the first 6 months then changed little the remaining time compared to control (p < 0.001 for each). The incidence of long-bone fractures, the average vertebral heights, the cortical thickness, bone pain and finally functional activity were similar to the control placebo group [28]. Taken together the study concluded that the fracture outcome, bone pain, and quality of life were improved with oral alendronate and were comparable to intravenous bisphosphonates at doses used [28].
A controlled trial treated severely affected osteogenesis imperfecta children under 3 years of age for a period of 12 months with intravenous pamidronate in 3 consecutive days for four to eight cycles, with an average cumulative dose of 12.4 mg/kg. The age-matched, severity-matched controls did not receive the treatment. BMD in treated children increased dramatically up to 227% (p < 0.001), and fracture rate decreased significantly (p < 0.01) compared to untreated control children [85]. Side effects were minor and as expected. This trial confirmed the intravenous pamidronate in very young and severely affected osteogenesis imperfecta children is safe and beneficial.
Intravenous pamidronate 10 mg/m2 per day administered for 1 year to types III and IV osteogenesis imperfecta children in a randomized controlled trial, increased significantly lumbar spine BMD Z-scores and volumetric vertebral size. Fracture rates decreased in upper extremities and not in the lower extremities, functional mobility and pain were not improved, and a second year extension of the therapy did not additionally significantly improve the bone density [86].
In a retrospective case–control study in children and adolescents with low BMD, who had no osteogenesis imperfecta and no metabolic bone disease, cumulative dose of oral alendronate was compared with DXA changes. The results indicated that alendronate does not improve bone density in children with primarily neuromuscular disease and without osteogenesis imperfecta compared to control patients with no treatment at all [87].
In a randomized placebo-controlled, multicenter trial, daily risedronate 2.5 or 5 mg for 1 year, in children 4–15 years with osteogenesis imperfecta, increased significantly lumbar spine BMD compared to control (p < 0.0001). The rate of clinical fractures decreased significantly as well after 1 year of therapy (p = 0.045). But in the follow up in years 2 and 3, the rate of clinical fractures did not change significantly in patients treated with risedronate compared to placebo-treated controls [88].
Results of these studies, and also safety issues, suggest that bisphosphonate therapy should be discontinue after 1–2 years of therapy.
Glucocorticoid-induced osteopenia
Glucocorticoid-associated osteoporosis in growing children is associated with a 20% increase in age-adjusted fracture rates [68],[69]. Glucocorticoids inhibit bone formation by decreasing the number of osteoblasts and increasing the rate of bone resorption by stimulating osteoclasts. Glucocorticoids decrease intestinal absorption and increase the renal excretion of Ca. In adults, a daily dose less than 7.5 mg glucocorticoids have been linked to such changes. In adults, alendronate effectively prevents glucocorticoid-induced osteoporosis [7],[89]. Data from uncontrolled studies, in children receiving glucocorticoids treated with bisphosphonates have demonstrated significant increases in spinal bone density Z-scores after intravenous bisphosphonates or oral alendronate [90]. In a small placebo-controlled study in children with chronic illnesses treated with glucocorticoids, oral alendronate 1–2 mg/kg body weight/week for one year was well tolerated and increased bone density and volumetric size of the lumbar spine, and decreased indexes of bone resorption but did not improve bone growth and the size of long bones [91]. Severe corticoid-induced bone loss in Duchenne muscular dystrophy was reduced with bisphosphonate therapy [59],[60].
Pediatric bone malignancies
Pamidronate and zoledronic acid are the most rigorously studied N-bisphosphonates in adult malignancies, in addition to reducing pain and reducing fracture incidence in bone metastatic cancers, they have also an antitumor activity. In preclinical trials in pediatric cancers, Zoledronic acid was used as an active anticancer agent, with low incidence or no significant side effects in neuroblastoma [19],[20], osteosarcoma [92], and in Ewing’s sarcoma [93],[94].
In a phase I clinical trial in children with recurrent/refractory neuroblastoma, zoledronic acid combined with cyclophosphamide resulted in prolonged disease stability in about 50% of cases. The maximum tolerated dose of 4 mg/m2/every 28 days was recommended since it was more effective than 2 mg/m2 dose. Most side-effects were transient and tolerable. However one case of osteosclerosis complicated by fracture was reported in this study [21].
In retrospective studies [75], pediatric patients with skeletal metastatic malignancies were treated at least with one dose of intravenous zoledronic acid in combination with chemotherapeutic regiments. Patients above 10 years age received the recommended adult dose of 4 mg/kg and those younger than 10 received between 0.08 – 0.16 mg/kg. Results of these studies confirmed that zoledronic acid alleviates pain in metastatic bone cancers, has the potential antitumor actions, and has low incidence of side effects.
In Ewing sarcomas, experimental and preclinical trials have indicated the benefit of bisphosphonates as adjuvant therapies [95]. In vitro, zoledronic acid significantly inhibits Ewing sarcoma [94] and osteosarcoma [92] cell lines invasiveness and cell cycles [93]. In mouse models, zoledronic acid inhibits the tumor development of Ewing sarcoma in bone and reduces the dissemination of lung metastasis. However zoledronic acid neither opposes the growth of already established metastasis, nor opposes the progression of the tumor in soft tissues in Ewing sarcoma models [94].
In preclinical animal models and in vitro studies of neuroblastoma, zoledronic acid stimulates natural killer T cells, thus inhibiting the growth of neuroblatoma tumor cells [20], and in combination with chemotherapeutic agents, both prevents and reduces bone metastasis [19]. A phase I study for new approaches in therapy of neuroblastoma (NANT) has concluded that 4 mg/m2/28 days zoledronic acid combined with cyclophosphamide will result in stability of most cases of neuroblastomas [21].
In retrospective studies on osteonecrosis in children related to chemotherapy, 1 year pamidronate [96] or on osteonecrosis unrelated to chemotherapy, one year zoledronic acid [97], improved pain, BMD, and motor function and opposed joint destruction.
Side-effects reported in pediatric bone malignancy are those already expected. These include initial phase reaction [29],[32],[33], transient hypophosphatemia and hypocalcemia, prevented with supplementation with calcium and vitamin D [21],[75].
Because of long half-life of zoledronic acid and secondary release of compounds, and possible inhibition of growth of long bones, long term safety is the major concern. Overall the improvement of the survival in pediatric cancer patients has yet to be determined and further study is needed. A French multicenter randomized phase III trial (OS2006- NTC00470223) is currently under way that might lead to establish appropriate pediatric dosages in bone malignancy.
Secondary amenorrhea in young girls
Anorexia Nervosa is associated in nearly 50% with severe bone loss, preferentially in the spine [84]. There is a relative hypogonadism, low IGF-1, relative hypercortisolemia, low leptin, and increase adiponectin. Limited data for anorexia nervosa [34] indicates that bisphosphonate treatment reduces bone turnover and increases bone density. Risedronate 35 mg/week for 12 months administered to adult female with anorexia nervosa, has improved significantly bone densities of spine and femoral neck [84]. Oral alendronate 10 mg daily in randomized placebo-controlled trial, has also increased significantly the femoral neck and lumbar spine BMD from baseline in adolescents with anorexia nervosa vs placebo-treated patients [98]. Estrogen/progestin therapy is ineffective in preventing or reversing bone loss in girls with anorexia nervosa [99]. Recombinant hIGF-1 increases BMD but does not increase BMD to normal levels and it still an experimental strategy [100]–[102]. Testosterone therapy in adults female does not improve bone density [34],[84] and should not be administered in young girls with anorexia nervosa. Weight gain in anorexia nervosa and exercise reduction in athletic girls typically leads to the restoration of menses [62],[64].
Overall there are limited data supporting improvement of bone loss by bisphosphonate therapy in secondary amenorrhea in adolescent girls. Thus, because of unknown teratogenic effects on the fetus, bisphosphonates use in adolescent girls with secondary amenorrhea is questionable [34],[62],[98].
Histiocytosis
In Langerhans cell histiocytosis, a retrospective study conducted in Japanese children aged 2.3–15.0 years, pamidronate administered intravenously at a median dose of 1.0 mg/kg/day for 3 days per cycle, between six to ten cycles at 4 to 8-week intervals, appeared to resolve the lesions in bone, skin, and soft tissues. In this study, one case of acute phase reaction, one case of uveitis, and two cases of hypocalcemia were reported in 16 children treated with pamidronate [30].
McCune-albright syndrome, fibrous dysplasia
Fibrous dysplasia is a rare disorder arising from GNAS mutations that results in bone marrow cell proliferation and in fibro-osseous tissues in bone and bone marrow. Limited studies have demonstrated benefits of pamidronate improving pain and markers of bone turnover [103],[104].
Bone losses in impaired mobility
Cerebral palsy is characterized by impaired movements and posture, arising from abnormalities in the central motor neurons, and resulting in high prevalence of osteoporosis in children. Data from multiple controlled trials and meta-analysis studies in children with cerebral palsy treated with pamidronate or risedronate, concluded the treatment improved the BMD and reduced significantly the fracture rate after 1 year therapy [105],[106], while in some trials the protective effects lasted beyond 4 years after the end of the 1-year therapy [107].
In Duchenne muscular dystrophy, other condition with impaired mobility, a retrospective analysis of patients with vertebral compression fractures treated with pamidronate or zoledronic acid demonstrated improvement in pain, and in BMD in vertebra. Prolonged glucocorticoid therapy in DMD combined with severe muscle weakness and impaired motility resulted in severe bone loss and vertebral compression fractures that was treated with bisphosphonate therapy [59],[60].
Spinal cord injuries are characterized by prolonged immobilization and muscle atrophy and result in rapid bone loss and high incidence of long bone fractures. Limited case reports have shown improvement of BMD with the use of bisphosphonates in spinal cord injury in adults and children [26],[108].
Bisphosphonates in in young girls with thalassemia, because of possibility of future pregnancy, should be carefully considered [71],[78],[109].
Conclusion
In summary simple non-nitrogen-containing bisphosphonates result in accumulations of toxic products that lead to osteoclastic cell death while nitrogen-containing bisphosphonates inhibit osteoclast functions and activity. Both types of bisphosphonates reduce bone turnover, while the rate of bone resorption is more reduced than the rate of bone formation. The degree of avidity for the bone tissue of particular bisphosphonate determines the duration of action of the bisphosphonate after discontinuation. While long-acting bisphosphonate are a better choice for adults, they might be an undesired choice for children with growing bone. Because of possible unknown teratogenic effects, the long half-life make the bisphosphonate a questionable medication for young girls. There is not sufficient long-term efficacy and safety data for bisphosphonate therapy in pediatric age group. However short-term use appears to improve bone density and pain in conditions such as osteogenesis imperfecta, chronic corticoid therapy, and bone malignancy.
The 2014 Cochrane Database Systemic Review confirmed the positive effects of bisphosphonates concluding that bisphosphonates increase bone density in children and adolescents with osteogenesis imperfecta. There is not enough data to conclude whether bisphosphonates improve clinical status by improving growth and functional mobility in osteogenesis imperfecta. However intravenous bisphosphonates are associated with improved fracture rate in extremities and heights of vertebras.
Rational behind the use of bisphosphonates in bone malignancies is based on selective accumulation in bone tissue, potent inhibition of bone resorption by inducing osteoclasts apoptosis and increasing osteoprotegerin (OPG) production, and antitumor effects of bisphosphonates. In pediatric cancers with bone involvement, the improvement of pain, the slowdown in metastatic progression, and stabilization of the primary disease by bisphosphonates, make these medications desirable. Multicenter randomized phase III trials for pediatric bone malignancies (French OS2006- NTC00470223) might lead to establishment of appropriate dosages, optimal methods and duration of therapy, and to determination of long term safety of bisphosphonate therapy in overall pediatric patients.
One can conclude that there is a need for more future randomized studies of bisphosphonate therapy in pediatric age group to propose better evidence based recommendations.
Abbreviations
- aBMD:
-
areal bone mineral density
- NTX:
-
Amino-terminal telopeptide of collagen cross-links
- DMD:
-
Duchenne muscular dystrophy
- OPG:
-
osteoprotegerin
- LS:
-
lumbar-sacral
References
Glorieux FH, Bishop N, Plotkin H, Chabot G, Lanoue G, Travers R: Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998, 339: 947–952.
Rauch F, Cornibert S, Cheung M, Glorieux FH: Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta. Bone 2007, 40: 821–827.
Ward L, Tricco AC, Phuong P, Cranney A, Barrowman N, Gaboury I, Rauch F, Tugwell P, Moher D: Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Cochrane Database Syst Rev 2007, 17(4):CD005324.
Bachrach LK, Ward LM: Clinical review: bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab 2009, 94: 400–409.
Dwan K, Phillipi CA, Steiner RD, Basel D: Bisphosphonates therapy for osyeogenesis imperfecta. Cochrane Database Syst Rev 2014, 7: CD005088.
Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RGG, Ebetino FH: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 2006, 18: 617–627.
Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J: Biochemical and molecular mechanisms of action of bisphosphonates. Bone 2011, 49: 34–41.
Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RGG, Rodan GA, Reszka AA: Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption and kinase activation in vitro . Proc Natl Acad Sci U S A 1999, 96: 133–138.
Halasy-Nagy JM, Rodan GA, Reszka AA: Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis. Bone 2001, 29: 553–559.
Sutherland KA, Rogers HL, Tosh D, Rogers MJ: RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteoclast apoptosis in vitro . Arthritis Res Ther 2009, 11: R58.
Benford HL, Frith JC, Auriola S, Mönkkönen J, Rogers MJ: Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol 1999, 56: 131–140.
Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ: Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells. Bone 2008, 42: 848–860.
Glatt M, Pataki A, Evans GP, Hornby SB, Green JR: Loss of vertebral bone and mechanical strength in estrogen-deficient rats is prevented by long-term administration of zoledronic acid. Osteoporos Int 2004, 15(9):707–715.
Weinstein RS, Roberson PK, Manolagas SC: Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009, 360: 53–62.
Jain N, Weinstein RS: Giant osteoclasts after long-term bisphosphonate therapy: diagnostic challenges. Nat Rev Rheumatol 2009, 5: 341–346.
Zhou Z, Guan H, Duan X, Kleinerman ES: Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma. Cancer 2005, 104(8):1713–1720.
Gaspar N, Di Giannatale A, Geoerger B, Redini F, Corradini N: Bone sarcomas: from biology to targeted therapies. Sarcoma Volume 2012, 301975: 1–18. 2012
Guan H, Zhou Z, Cao Y, Duan X, Kleinerman EK: VEGF165 promotes the osteolytic bone destruction of Ewing’s sarcoma tumors by up-regulating RANKL. Oncol Res 2009, 18(2–3):117–125.
Peng H, Sohara Y, Moats RA, Nelson MD, Groshen SG, Ye W, Reynolds CP, DeClerck YA: The activity of zoledronic acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. Cancer Res 2007, 67: 9346–9355.
Di Carlo E, Bocca P, Emionite L, Cilli M, Cipollone G, Morandi F, Raffaghello L, Pistoia V, Prigione I: Mechanisms of the antitumor activity of human Vγ9Vδ2 T cells in combination with zoledronic acid in a preclinical model of neuroblastoma. Moleculartherapy Org 2013, 21(5):1034–1043.
Russell HV, Groshen SG, Ara T, DeClerck YA, Hawkins R, Jackson HA, Daldrup-Link HE, Marachelian A, Skerjanec A, Park JR, Katzenstein H, Matthay KK, Blaney SM, Villablanca JG: A phase I study of zoledronic acid and low dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study. Pediatr Blood Cancer 2011, 57(2):275–282.
Rauch F, Travers R, Plotkin H, Glorieux FH: The effects of intravenous pamidronate on the bone tissue of the children and adolescents with osteogenesis imperfecta. J Clin Invest 2002, 110: 1293–1299.
Rauch F, Plotkin H, Zeitlin L, Glorieux FH: Bone mass, size, and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy. J Bone Miner Res 2003, 18(4):610–614.
Rauch F, Munns C, Land C, Glorieux FH: Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab 2006, 91: 1268–1274.
Rauch F, Munns C, Land C, Glorieux FH: Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of treatment discontinuation. J Clinic Endocrinol Metab 2006, 91: 1268–1274.
Ooi HL, Briody J, McQuade M, Munns CF: Zoledronic acid improves bone mineral density in pediatric spinal cord injury. J Bone Miner Res 2012, 27: 1536–1540.
Reid IR, Black DM, Eastell R, Bucci-Rechtweg C, Su G, Hue TF, Mesenbrink P, Lyles KW, Boonen S: Reduction in the risk of clinical fractures after a single dose of zolendronic 5 milligrams. J Clin Endocrinol Metab 2013, 98: 557–563.
Ward LM, Rauch M, Whyte MP, D’Astous J, Gates PE, Grogan D, Lester EL, McCall RE, Pressly TA, Sanders JO, Smith PA, Steiner RD, Sullivan E, Tyerman G, Smith-Wright DL, Verbruggen N, Heyden N, Lombardi A, Glorieux FH: Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab 2011, 96: 355–364.
Munns CF, Rajab MH, Hong J, Briody J, Högler W, McQuad M, Little DG, Codwell CT: Acute phase response and mineral status following low dose intravenous zoledronic acid in children. Bone 2007, 41: 366–370.
Morimoto A, Shioda Y, Imamura T, Kanegane H, Sato T, Kudo K, Nakagawa S, Nakadate H, Tauchi H, Hama A, Yasui M, Nagatoshi Y, Kinoshita A, Miyaji R, Anan T, Yabe M, Kamizono J: Nationwide survey of bisphosphonate therapy for children with reactivated langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 2011, 56: 110–115.
Rizzoli R, Burlet N, Cahall D, Delmas PD, Eriksen EF, Felsenberg D, Grbic J, Jontell M, Landesberg R, Laslop A, Wollenhaupt M, Papapoulos S, Sezer O, Sprafka M, Reginster JY: Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone 2008, 42: 841–847.
Munns CF, Rauch F, Mier RJ, Glorieux FH: Respiratory distress with pamidronate treatment in infants with severe osteogenesis imperfecta. Bone 2004, 35: 231–234.
Munns CF, Rauch F, Ward L, Glorieux FH: Maternal and fetal outcome after long-term pamidronate treatment before conception: a report of two cases. J Bone Miner Res 2004, 19: 1742–1745.
Miller KK, Grieco KA, Mulder J, Grinspoon S, Mickley D, Yehezkel R, Hertzog DB, Klibanski A: Effects of risedronate on bone density in anorexia nervosa. J Clinic Endocrinol Metab 2004, 89(8):3903–3906.
Papapoulos SE, Cremers CL: Prolonged bisphosphonate release after treatment in children. N Engl J Med 2007, 356: 1075–1076.
Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A: Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 1999, 60: 68–73.
Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S: Bisphosphonate-induced osteopetrosis. N Eng J Med 2003, 349: 457–463.
Battaglia S, Dumoucel S, Chesneau J, Heymann MF: Impact of oncopediatric dosing regimen of zoledronic acid on bone growth: preclinical studies and case report of an osteosarcoma pediatric patient. J Bone Miner Res 2011, 26(10):2439–2451.
Mayranpaa MK, Tamminen IS, Kroger H, Makitie O: Bone biopsy findings and correlation with clinical, radiological, and biochemical parameters in children with fractures. J Bone Miner Res 2011, 26: 1748–1758.
Bianchi ML: Osteoporosis in children and adolescents. Bone 2007, 41: 486–495. 2011
Goulding A, Grant AM, Williams SM: Bone and body composition of children and adolescents with repeated forearm fractures. J Bone Miner Res 2005, 20: 2090–2096.
Farr JN, Amin S, Melton LJ III, Kirmani S, McCready LK, Atkinson E, Müller R, Sundeep K: Bone strength and structural deficits in children and adolescents with a distal forearm fracture due to mild trauma. J Bone Miner Res 2013, doi:10.1002/jbmr.2071.
Bishop N, Braillon P, Burnham J, Cimaz R, Davies J, Fewtrell M, Hogler W, Kennedy K, Makitie O, Mughal Z, Shaw N, Vogiatzi M, Ward K, Bianchi ML: Dual-energy X-ray absorptiometry assessment in children and adolescents with diseases that may affect the skeleton: the 2007 ISCD pediatric official positions. J Clin Densitom 2007, 11: 29–42.
Rauch F, Lalic L, Roughley P, Glorieux FH: Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfect. J Bone Miner Res 2010, 25: 1367–1374.
Glorieux FH, Moffat P: Osteogenesis imperfecta, an ever-expanding conundrum. J Bone Miner Res 2013, 28(7):1519–1522.
Sillence DO, Senn A, Danks DM: Genetic heterogeneity in osteogenesis imperfecta. J Medic Genet 1979, 16: 101–116.
Van Dijk FS, Sillence DO: Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A 2014, 8(10):36545.
Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D, Lee G, Kim HN, Lee HR, Eom HH, Lee ZH, Kim OH, Park WY, Park SS, Ikegava S, Yoo WJ, Choi IH, Kim JW: A single recurrent mutation in the 5′-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet 2012, 91(2):343–348.
Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R: Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002, 17(1):30–38.
Ward LM, Rauch F, Travers R, Chabot G, Azouz EM, Lalic L, Roughley PJ, Glorieux FH: Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 2002, 31(1):12–18.
Rauch F, Glorieux FH: Osteogenesis imperfecta. Lancet 2004, 363: 1377–1385.
Kelley BP, Malfait F, Bonafe L, Baldridge D, Homan E, Symoens S, Willaert A, Elcioglu N, Van Maldergem L, Velleren-Dumoulin C, Gillerot Y, Napierala D, Krakow D, Beighton P, Superti-Furga A, De Paepe A, Brendan L: Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome. J Bone Min Res 2011, 26(3):666–672.
Malfait F, Hakim AJ, De Paepe A, Grahame R: The genetic basis of joint hypermobility syndromes. Rheumatology 2006, 45: 502–507.
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ: Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Support Group (UK). Am J Med Genet 1998, 77: 31–37.
Bank RA, Robins SP, Wijmenga C, Breslau-Siderius LJ, Bardoel AF, van der Sluijs HA, Pruijs HE, Tekoppele JM: Defective collagen crosslinking in bone, but not in ligament or cartilage, in bruck syndrome: indications for a bone-specific telopeptide lysyl hydroxylaseon chromosome 17. Proc Natl Acad Sci U S A 1999, 96: 1054–1058.
Milewicz DM: Molecular genetics of Marfan syndrome and Ehlers-Danlos type IV. Curr Opin Cardiol 1998, 13(3):198–204.
Robinson PN, Maurice G: The molecular Genetic of Marfan syndrome and related microfibrillopathies. J Med Genet 2000, 37: 9–25.
Narumi S, Numakura C, Shiihara T, Seiwa C: Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray. Am J Med Gen A 2009, 152A(1):133–140.
Sbrocchi AM, Rauch F, Jacob P, McCormick A, McMillan HJ, Matzinger MA, Ward LM: The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with duchenne muscular dystrophy. Osteoporosis Int 2012, 23: 2703–2711.
Gordon KE, Dooley JM, Sheppard KM, MacSween J, Esser MJ: Impact of bisphosphonates on survival for patients with duchenne muscular dystrophy. Pediatrics 2011, 127: e.353-e.358.
Liu JH, Bill AH: Stress-associated or functional hypothalamic amenorrhea in the adolescent. Ann N Y Acad Sci 2008, 1135: 179–184.
Gordon CM: Functional hypothalamic amenorrhea. N Engl J Med 2010, 363: 365–371.
Meczekalski B, Podfigurna-Stopa A: Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecolo Endocrinol 2008, 24: 4–11.
Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP: American college of sports medicine position stand: the female athlete triad. Med Sci Sports Exerc 2007, 39: 1867–1882.
De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, Gibbs JC, Olmsted M, Goolsby M, Matheson G: Female athlete S coalition consensus statement on treatment and return to play of the female athlete triad: 1st international conference held in San Francisco, California, May 2012 and 2nd international conference held in Indianapolis, Indiana, May 2013. Br J Sports Med 2014, 48: 289.
Hoek HW, van Hoeken D: Review of the prevalence and incidence of eating disorders. Int J Eat Disord 2003, 34: 383–396.
Yager J, Anderson AE: Anorexie nervosa. New Engl J Med 2005, 353: 1481–1488.
Canalis E, Mazziotti G, Giustina A, Bilzekian JP: Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007, 18: 1319–1328.
Van Staa TP, Cooper HG, Leufkens HG, Bishop N: Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003, 18: 913–918.
Agastiniotis M, Modell B: Global epidemiology of hemoglobin disorders. Ann N Y Acad Sci 1998, 850: 251–259.
Rund D, Rachmilewitz E: β thalassemia. N Engl J Med 2005, 353: 1135–1146.
Morabito N, Gaudio A, Lasco A, Atteritano M, Pizzoleo MA, Cincotta M, La Rosa M, Guarino R, Meo A, Frisina N: Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Min Res 2004, 19(5):722–727.
Vogiatzi M, Mackin E, Fung EB, Cheung AM, Vichinsky E, Olivieri N, Kirby M, Kwiatkowski JL, Cunningham M, Holm IA, Lane J, Schneider R, Fleisher M, Grady RW, Peterson CC, Giardina PJ: Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Min Res 2009, 24: 543–557.
Fung EB, Vichinsky EP, Kwiatkowski JL, Huang J, Bachrach LK, Sawyer AJ, Zemel BS: Characterization of low bone mass in young patients with thalassemia by DXA, pQCT and markers of bone turnover. Bone 2011, 48(6):1305–1312.
August KJ, Dalton A, Katzenstein HM, George B, Olson TA, Wasilewski-Masker K, Rapkin LB: The use of zoledronic acid in pediatric cancer patients. Pediatr Blood Cancer 2011, 56: 610–614.
Taylor R, Knowles HJ, Athanasou NA: Ewing sarcoma cells express RANKL and support osteoclastogenesis. J Pathol 2011, 225(2):195–202.
Chad KE, McKay HA, Zello GA, Bailey DA, Faulkner RA, Snyder RE: The effect of a weight-bearing physical activity program on bone mineral content and estimated volumetric density in children with spastic cerebral palsy. J Pediatr 1999, 135: 115–117.
De Sanctis V: Growth and puberty and its management in thalassemia. Horm Res 2002, 58(Suppl;1):72–79.
Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M: Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008, 122: 398–417.
Edouard T, Glorieux FH, Rauch F: Predictors and correlates of vitamin D Status in children and adolescents with osteogenesis imperfecta. J Clin Endocrinol Metab 2011, 96: 3193–3198.
Tashjian AH, Gagel RF: Teriparatide [Human PTH(1–34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res 2006, 21: 354–365.
Teitelbaum SL, Ross FP: Genetic regulation of osteoclast development and function. Nat Rev Genet 2003, 4: 638–649.
Lamoureux F, Richard P, Wittrant Y, Battaglia S, Pilet P, Trichet V, Blanchard F, Gouin F, Pitar B, Heymann D, Redini F: Therapeutic relevance of osteoprotegerin gene-therapy in osteosarcoma: blockade of vicious cycle between tumor cell proliferation and bone resorption. Cancer Res 2007, 67(15):7308–73–18.
Miller KK, Meenaghan E, Lawson EA, Misra M, Gleysteen S, Schoenfeld D, Hertzog D, Klibanski A: Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2011, 96(7):2081–2088.
Plotkin H, Rauch F, Bishop NJ, Monpetit K, Ruck-Gibis J, Travers R, Glorieux FH: Pamidronate treatment of severe osteogenesis imperfect in children under 3 years of age. J Clin Endocrinol Metab 2000, 85: 1846–1850.
Letocha AD, Cintas HL, Troendle JF, Reynolds JC, Cann EC, Chernoff EJ, Hill SC, Gerber LH, Marini JC: Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res 2005, 20: 977–986.
Dominguez-Bartmess SN, Tandberg D, Cheema AM, Szalay EA: Efficacy of Alendronate in the treatment of low bone density in the pediatric and young adult population. J Bone Joint Surg Am 2012, 94(10):e62(1–6).
Bishop N, Adami S, Ahmed SF, Anton J, Arundel P, Burren CP, Devogelaer JP, Hangartner T, Hossozu E, Lane JM, Lorenc R, Mäkitie O, Munns CF, Paredes A, Pavlov H, Plotkin H, Raggio CL, Reyes ML, Schoenau E, Semler O, Sillence DO, Steiner RD: Risedronate in children with osteogenesis imperfecta: a randomized, double-blind, placebo-controlled trial. Lancet 2013, 382: 1424–1432.
De Nijs RNJ, Jacobs JWG, Lems WF, Laan RFJ, Algra A, Huisman AM, Buskens E, de Laet CED, Oostveen ACM, Geusens PPMM, Bruyn GAW, Dijkmans BAC, Bijlsma JWJ: Alendronate or alfacalcidol in glucocorticoide-induced osteoporosis. N Engl J Med 2006, 355: 675–684.
Noguera A, Ros JB, Pavia C, Alcover E, Valls C, Villaronga M, González E: Bisphosphonates, a new treatment for glucocorticoid-induced osteoporosis in children. J Pediat Endocrinol Metab 2003, 16: 529–536.
Rudge S, Hailwood S, Horne A, Lucas J, Wu F, Cundy T: Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment. Rheumatology 2005, 44: 813–818.
Kubista B, Trieb K, Sevelda F, Toma C: Anticancer effects of zoledronic acid against human osteosarcoma cells. J Orthop Res 2006, 24(6):1145–1152.
Odri GA, Dumoucel S, Picarda G, Battaglia S: Zoledronic acid as a new adjuvant therapeutic strategy for Ewing’s sarcoma patients. Cancer Res 2010, 70(19):7610–7619.
Odri G, Kim PP, Lamoureux F, Charrier C, Battaglia S, Amiaud J, Heymann D, Guin F, Redini F: Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration. BMC Cancer 2014, 14: 169.
Anninga JK, Cleton-Jansen AM, Hassan B, Amary MF, Baumhoer D, Blay JY, Brugieres L, Ferrari S, Jürgens H, Kempf-Bielack B, Kovar H, Myklebost O, Nathrath M, Picci P, Riegman P, Schilham MW, Soliman R, Stark DP, Strauss S, Sydes M, Tarpey P, Thomas D, Whelan J, Wilhelm M, Zamzam M, Gelderblom H, Bielack SS: Workshop report on the 2nd Joint ENCCA/EuroSARC European bone sarcoma network meeting: integration of clinical trials with tumour biology. Clin Sarcoma Res 2014, 4: 4. [http://www.clinicalsarcomaresearch.com/content/4/1/4]
Leblicq C, Laverdière C, Décarie JC, Delisle JF, Isler MH, Moghrabi A, Chabot G, Alos N: Effectiveness of pamidronate as treatment of symptomatic osteonecrosis occurring in children treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 2013, 60(5):741–747.
Padhye B, Dalla-Pozza L, Little DG, Munns CF: Use of zolendronic acid for treatment of chemotherapy-related osteonecrosis in children and adolescents: a retrospective analysis. Pediatr Blood Cancer 2013, 60(9):1539–1545.
Golden NH, Iglesias EA, Jacobson MS, Carey D, Schebendach J, Hertz S, Shenker IR: Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2005, 90: 3179–3185.
Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR: The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol 2002, 15(3):135–143.
Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A: Effect of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab 2002, 87: 2883–2891.
Misra M, Klibanski A: Bone metabolism in adolescent with anorexia nervosa. J Endocrinol Invest 2011, 34(4):324–332.
Misra M, Klibanski A: Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol 2014, 2(7):581–592.
Chapurlat RD, Delmas PD, Liens D, Meunier PJ: Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. J Bone Miner Res 1997, 12: 1746–1752.
Chapurlat RD, Hugueny P, Delmas PD, Meunier PJ: Treatment of fibrous dysplasia of bone with intravenous pamidronate: long-term effectiveness and evaluation of predictors of response to treatment. Bone 2004, 35: 235–242 y.
Henderson RC, Lark RK, Kecskemethy HH, Miller F, Harcke HT, Bachrach SJ: Bisphosphonates to treat osteopenia in children with quadriplegic cerebral palsy: a randomized, placebo-controlled clinical trial. J Pediatr 2002, 141: 644–651.
Fehlings D, Switzer L, Agarwal P, Wong C, Sochett E, Stevenson R, Sonnenberg L, Smile S, Young E, Huber J, Milo-Manson G, Kuwaik GA, Gaebler D: Informing evidence-based clinical practice guidelines for children with cerebral palsy at risk of osteoporosis: a systematic review. Dev Med Child Neurol 2012, 54: 106–116. 2012
Bachrach SJ, Kecskemethy HH, Hrcke HT, Hossain J: Decreased fracture incidence after 1 year of pamidronate treatment in children with spastic quadriplegic cerebral palsy. Dev Med Child Neurol 2010, 52(9):837–842. 2010
Bryson JE, Gourlay ML: Bisphosphonate use in acute and chronic spinal cord injury: a systematic review. J Spinal Cord Med 2009, 32: 215–225.
Giusti A: Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomized controlled trials. J Bone Miner Metab published online April 2014 [Epub ahead of print].
Author information
Authors and Affiliations
Corresponding author
Additional information
Competing interests
The authors declare that they have no competing interests.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Eghbali-Fatourechi, G. Bisphosphonate therapy in pediatric patients. J Diabetes Metab Disord 13, 109 (2014). https://doi.org/10.1186/s40200-014-0109-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s40200-014-0109-y