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Bisphosphonate treatment of pediatric bone disease

The science of measuring bone mineral density has developed rapidly and, with it, an improved understanding of the efficacy and safety of various therapeutic interventions in adults. In contrast, the meaning and precision of such measurements in
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  Phyllis W. Speiser 1 , Cheril L. Clarson 2 , Erica A. Eugster 3 , Stephen F. Kemp 4 , Sally Radovick 5 , Alan D. Rogol 6 , Thomas A. Wilson 7 , on behalf of the LWPES Pharmacy and Therapeutic Committee 1 Schneider Children’s Hospital and New York University School of Medicine, New Hyde Park, NY 11040, 2 Children’s Hospital of Western Ontario, London, Ontario, Canada N6C2V5, 3 Dept of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, 4 Dept of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, 5 Dept of Pediatrics, University of Chicago School of Medicine, Chicago, IL 60637, 6 Department of Pediatrics, University of Virginia, Charlottesville, VA 22908, 7 Dept of Pediatrics, State University of New York at Stony Brook, Health Sciences Center, Stony Brook, NY 11794 Corresponding Author: Phyllis W. Speiser , Division of Pediatric Endocrinology, Schneider Children’s Hospital, 269-01 76th Ave., New Hyde Park, NY 11040, Phone: 718-470-3290, FAX: 718-470-4565, E-mail: Bisphosphonate Treatment of Pediatric Bone Disease Introduction Bisphosphonates have been used in the treatment of bone disease in adults for several decades. Approved indications for bisphosphonate therapy in the US now include osteoporosis and prevention of osteoporosis, Paget’s disease, osteolytic bone lesions of malignancy and hypercalcemia. Curiously, even among adult healthcare providers there is under-utilization of diagnostic procedures and available therapies for individuals at risk for osteopenia and osteoporosis. A recent systematic literature review showed that only about 32% of patients with fragility fractures had been screened for osteoporosis. Among those patients diagnosed with osteoporosis only about 18% had been counseled about calcium and vitamin D intake, and even fewer were prescribed bisphosphonates (1).The use of these agents in children has been restricted largely to clinical trials for select conditions associated with early onset of low bone density. In this report, we review the present state of knowledge regarding the use of bisphosphonates during childhood to ameliorate the skeletal abnormalities associated with osteogenesis imperfecta, idiopathic juvenile osteoporosis, fibrous dysplasia of bone and children with moderate to severe cerebral palsy. Other therapeutic uses will be touched upon briefly. Measuring Bone Mineral Density Before discussing treatment for low bone density, it is helpful to understand the methodological problems inherent in the measurements used to define low bone mineral density and to follow the efficacy of bisphosphonate (or other) treatment. Bone mass can be quantified in several ways. Plain radiographs are very insensitive to bone loss because approximately 30% of the bone mass must be lost before the plain film can detect it (2). In addition, precision is poor and the radiation dose relatively high.Quantitative computed tomography (QCT) is an excellent technique to determine actual volumetric bone mineral density (vBMD) and to distinguish trabecular from cortical bone. The use  Abstract T   he science of measuring bone mineral density has developed rapidly and, with it, an improved understanding of the efficacy and safety of various therapeutic interventions in adults. In contrast, the meaning and precision of such measurements in children are equivocal, and the concept of treatment for low bone density in the young patient is still largely undecided. In this report we review the present state of knowledge regarding the use of bisphosphonates during childhood to ameliorate the skeletal abnormalities associated with osteogenesis imperfecta, idiopathic juvenile osteoporosis,  fibrous dysplasia of bone and cerebral palsy. Because of the  paucity of long-term studies among children regarding the safety and efficacy of these drugs, it is difficult to formulate strong evidence-based recommendations for their use, except  perhaps in children with osteogenesis imperfecta. Ref: Ped. Endocrinol. Rev. 2005;2:87-96 Key words : Bone density; Disphosphonates; Metabolic bone disease; Osteoporosis; Osteogenesis imperfecta; Fibrous dysplasia; Idiopathic juvenile osteoporosis; Cerebral palsy  87 Pediatric Endocrinology Reviews (PER) n   Volume 3   n   No. 2   n   December 2005  of this method in children is limited by the high radiation dose (50 to 100 mrem) (3). A recent modification is peripheral QCT (pQCT) for the appendicular skeleton in children. The radiation dose is much diminished (~3 mrem) and the quantity of bone and bone dimensions can be distinguished. These features permit one to make an estimate of bone strength (resistance to bending). The latter parameter is related to fracture risk. Pediatric data bases have been constructed for pQCT (4), however, it is important to recognize that no epidemi however, it is important to recognize that no epidemiologic data are available for risk of fracture in children based on any imaging technique. The most commonly available technique is dual x-ray absorptiometry (DXA), which uses the principle of differential attenuation of two x-ray beams to determine BMD. The radiation dose is low (~20 mrem), the scanning time oftenmay be less than 5 min depending on the hardware and software used and the precision is high. A number of pediatric data bases (including pubertal ages) exist (5,6). The limitation of this technique is that a real BMD (not true volumetric BMD) is determined. That is, the bone mineral content of a particular region of interest is divided by the area (surface) of the bone. The depth of surrounding fat tissue can make a large difference, as in anorexia nervosa or, the much more common obesity. The report is in g/cm 2  , ignoring the third dimension (depth) that is critical to true volumetric BMD as reported by CT techniques (7). The most important confounding factor is that BMD by this technique apparently increases as the bones get larger. Thus, smaller children will have lower BMD (and z score) than larger children, even though the volumetric BMD is equal. In addition this technique does not account for the location of the bone, that is, on the periosteal surface or the endosteal surface. The farther the bone is located from the center of the marrow cavity, the greater the resistance to bending, the stronger the bone and the lesser the fracture risk (8).It is important to recognize that most BMD facilities accustomed to servicing an adult population report t score, which compares the subject to same sex individuals at 20 years of age. For reasons described above and because most adolescents and children will not yet have attained peak bone mass, younger subjects cannot be compared to 20 year olds. Instead of using t scores, pediatric-specific databases must be employed that provide a z score appropriate for a cross-sectional sample of healthy subjects of the same chronologic age. Some investigators believe that bone age, weight age or height age are better criteria for z score comparison, rather than chronologic age. Other techniques include quantitative ultrasound, especially at the calcaneus. This technique is probably not as accurate as other quantitative techniques based on x-rays and requires additional consideration of anthropometric measurements (9). Digital radiogrammetry had been used for a number of years as a research tool at a few centers. It is not widely available or standardized against some of the more modern technologies. Pharmacology of Bisphosphonates Synthetic analogs:  Bisphosphonates (Bp, also known as diphosphonates) are synthetic analogs of naturally occurring pyrophosphates. Alkaline phosphatase cleaves pyrophosphate and prevents it from associating with the calcified bone matrix. Bisphosphonates have two phosphate bonds on the same carbon ( Figure 1 ), resulting in a compound resistant to cleavage by alkaline phosphatase and capable of attaching to calcium-containing crystals in bone. Each carbon atom has two additional bonds available, making possible many permutations to this basic structure. Changes in these side chains (designated R in Figure 1 ) can lead to extensive changes in their physicochemical, biological, toxicological and therapeutic characteristics. Table 1 illustrates select bisphosphonate structures and relative potencies. O- R’ O-| | |O = P - C - P = O| | |O- R’ O- Figure 1 : Structure of Bisphosphonate Table 1: Characteristics of Select Bisphosphonates DrugR’ side chainR’’ side chainPotency Etidronate-OH-CH31Clondronate-Cl-Cl10Pamidronate-OH-CH2-CH2-NH2100Alendronate-OH-(CH2)3-NH2500Ibandronate-OH-CH 2 -CH 2 -N-CH 3 |  (CH 2 ) 4 -CH 3 1000Risedronate 2000Zoledronate10,000Risedronate SodiumC 7 H 10 NO 7 P 2 NaZoledronic AcidC 5 H 10 N 2 O 7 P 2 88 Pediatric Endocrinology Reviews (PER) n   Volume 3   n   No. 2   n   December 2005 Bisphosphonates in Pediatric Bone Disease  Mechanism of action : As noted, because bisphosphonates are structurally related to pyrophosphate, they have an affinity for bone mineral. Once administered to adults, they accumulate predominantly in osseous tissue with a half-life of more than 10 years (10). The exact half-life in children is unknown. There are two major biological effects: at therapeutic doses there is inhibition of bone resorption; whereas at higher doses, inhibition of mineralization may occur (11). To be effective in treating osteoporosis, inhibition of bone resorption should predominate, thus making it important that doses be not too high. Nitrogen-containing bisphosphonates (e.g., alendronate, pamidronate, zoledronic acid) are taken up by mature osteoclasts and inhibit an enzyme of the mevalonate pathway, farnesyl pyrophosphate synthetase (12). Non-nitrogen-containing Bps (e.g., clodronate, etidronate, tiludronate) are converted intracellularly to non-hydrolyzable analogues of ATP (13). These analogues are toxic to the cells, resulting in inhibition of pyrophosphate synthesis. This leads to inhibition of prenylation of small GTP-binding proteins responsible for cytoskeletal integrity with resulting apoptosis of the osteoclasts (14). Effects on osteoblasts (15,16) as well as osteoclasts (17-19) have been documented. The precise mechanism by which bisphosphonates reduce bone resorption and increase bone mass remains unclear. It may depend on the induction of osteoclast apoptosis, but there is also evidence that the anti-absorptive action of bisphosphonates does not require osteoclast apoptosis. Furthermore, it is not known why these drugs may ameliorate bone pain so rapidly after infusion, an effect that cannot be explained by cessation of microfractures. Although it has been thought that the action of Bps was limited to inhibition of bone resorption, there is some evidence that they may also have an indirect effect on bone formation (20). The first bisphosphonate to be studied extensively was etidronate. The dose required for etidronate to inhibit bone resorption was quite high, and in fact was near the dose that impairs normal mineralization. Newer compounds are up to 10,000 times more powerful in inhibiting bone resorption without a large difference in inhibition of mineralization. One of the factors important in terms of function is the type length of the aliphatic side chain; a backbone of 4 carbons is most active, as in alendronate. Cyclic bisphosphonates are also quitemost potent, especially if there is a nitrogen in the ring (e.g., risedronate). Table 1  shows the relative potencies of select bisphosphonates. Modes of administration:  The bisphosphonates most often used for their antiresorptive effects have been given orally to adults by daily administration. This method of administration has been somewhat problematic because of the dosing schedule and because of the need to take the medication on an empty stomach. The patient must also remain upright for up to an hour after ingestion in order to minimize potential adverse gastrointestinal events, namely esophagitis. The pills cannot be chewedor crushed, but must be swallowed whole or crushed and administered by nasogastric or gastric tube. A new oral solution (only available as alendronate in the US) facilitates administration to patients who cannot swallow pills. Oral bisphosphonates that allow administration to adults weekly or monthly (21,22)(e.g., ibandronate administered every 2 to 3 months) dosing have simplified their use with similar safety profiles and slightly better efficacy, but compliance issues remain. There is little or no information about the use of these intermittent oral preparations in children. Intravenous preparations, principally pamidronate, have been used in pediatric and adult patients with critically low bone density and frequent fractures (see below). The latter route obviates problems with absorption and gastrointestinal toxicity. In addition, there are now more data on safety and efficacy among children treated with the intravenous drugs than with oral preparations. Bioavailability and half-life:  Bps have low bioavailability, ranging from a few percent to <1% for some of the newer compounds. Higher intestinal pH increases Bp absorption, while lower pH, induced by orange juice and/or coffee consumption, decrease drug absorption. Calcium-containing products also impede absorption.When administered intravenously, bisphosphonates are usually given every 3 to 4 months (range 1 to 6 months). The newest generation of bisphosphonates has been administered even less frequently, even once per year in adults. They circulate in plasma bound to protein (23), although the effect of this binding has not been well characterized.Once in the circulation Bps are cleared rapidly, predominantly as a result of uptake by bone. It appears there is complete first-pass extraction by the skeleton (24). Once in the skeleton, they are released only as the result of bone turnover (25). Eventually, all Bps are excreted unaltered. These drugs should be used with caution in patients with renal insufficiency (26). Clinical Trials in Children Osteogenesis Imperfecta (OI) : OI is a congenital bone disease caused in most cases by a variety of heritable defects involving the synthesis of type I collagen (27). The hallmark of the disorder is brittle bones resulting in unremitting fractures, pain and skeletal deformities. Based on clinical features, several different forms of OI have been described. The srcinal Sillence classification scheme recognized 4 subgroups of OI, types I through IV (28). An expanded classification system has since been proposed, based on specific histologic and molecular genetic findings in additional subsets of patients with OI (29-31). Even with the newer numeric classification, some characteristics of the various types of OI overlap, and there is no consensus as to the features of each form of the disease (32). Moreover, some patients with features of OI do not have demonstrable mutations in the type I collagen gene, implicating other genetic causes of these phenotypes. It is 89 Pediatric Endocrinology Reviews (PER) n   Volume 3   n   No. 2   n   December 2005 Bisphosphonates in Pediatric Bone Disease  beyond the scope of this discussion to describe all the variants of OI in detail. Examples of two of the more severe types are given here.Type II OI is a lethal form of the disease, in which in utero fractures and thoracic deformity result in asphyxiation before or shortly after birth. Children with non-lethal but severe OI, typically type III, present with early and often atraumatic fractures, severe osteoporosis, progressive loss of mobility, deformities and chronic pain. Commonly associated features include blue sclera, growth retardation, kyphoscoliosis, excessive sweating, dentinogenesis imperfecta and hearing loss beginning in adolescence (33). It is estimated that by the age of 13 years, 50% of individuals affected with severe OI will have lost independent mobility. Until the advent of the bisphosphonates, no effective pharmacologic treatment for OI existed (34). The first case reports of the beneficial effects of bisphosphonates in children with OI appeared in the literature in the 1980’s (35,36). Since that time, numerous clinical trials have been conducted with remarkably consistent results. Although both oral and parenteral forms of bisphosphonates have been used, the vast majority of studies have involved intravenous pamidronate, administered in cycles ranging from every 1 to every 6 months. To date, results from bisphosphonate treatment of well over 200 infants and children with OI ranging in age from 2 months to the late teens have been published collected. Results from the more recent of these trials are shown in Table 2  (37-51). The length of treatment has varied, with outcomes currently available for up to 9 years of therapy in a small number of children (38) . Thus far, not a single prospective, randomized, placebo-controlled study employing bisphosphonates for OI has been published, although such studies are underway (52). Treatment efficacy, OI : Variations in treatment protocols as well as in the clinical features of participating subjects make inter-study comparisons difficult ( Table 2 ). However, several repetitive themes regarding the impact of bisphosphonates in this patient population have emerged. With rare exceptions (40) bone mineral density dramatically increases during treatment by approximately 50% to >120% over baseline, with an average increase in z-scores of around +2.6. The annualized and fracture rate diminishes in the majority of patients in whom this has been investigated, although interpretation is complicated by the potential presence of undiagnosed fractures and the known decrease in fracture frequency in children with OI with increasing age. Among children younger than 3 years, the annual fracture rate decreased by about 60% (2.6 ± 2.5 in children receiving pamidronate as compared with 6.3 ± 1.6 in untreated historical controls) (45). Commonly observed radiographic changes in treated patients include augmentation of vertebral height and greater cortical thickness. These changes are substantiated by bone biopsies (19,53).In addition to these salutary effects, a significant height gain was observed in a spectrum of OI patients after 4 years of pamidronate therapy (54) Grip strength also increases within the first 4 months of treatment (43,55). Although difficult to quantify, virtually all investigators note decreased bone pain and increased mobility. Anecdotal vignettes included in several reports effectively highlight the compelling improvements in quality of life experienced by children with OI receiving bisphosphonate therapy and their families. Recent trials have begun to include children with less severe forms of OI. Such studies have also demonstrated increased bone mineral density and fewer fractures (56). Bone biopsies performed in children with OI who have been treated with pamidronate have revealed a gain in cortical thickness, and in the absolute number, but not the thickness of trabeculae in cancellous bone (19). Idiopathic Juvenile Osteoporosis (IJO) : IJO is a rare and enigmatic form of childhood osteoporosis of unknown etiology (57). It is a condition of variable severity characterized by vertebral compression fractures and fractures of the metaphyses of long bones. Affected patients often have difficulty walking and significant bone pain. Histomorphometry of the iliac crest samples from children with IJO show >50% reduction in cancellous bone volume, with reduced trabecular thickness and number compared with age-matched controls (58) Additionally, the bone formation rate at the endocortical surface is decreased (59). Features that differentiate IJO from OI include the presence of metaphyseal new bone formation that has been termed “neoosseous porosis” (60) lower bone turnover in IJO (58) and a pattern of spontaneous remission after the onset of puberty (61). The diagnosis of IJO is one of exclusion. Treatment of IJO has historically been confined to supportive measures such as physical therapy and optimization of calcium and vitamin D intake. However, favorable case reports of bisphosphonates in this setting have led to considerable interest regarding their use (62). As in OI, both oral and parenteral preparations have been utilized, although no controlled trials have been performed. Results from up to 8 years of treatment are available in a small number of children with IJO (63). Treatment efficacy, IJO : Nearly all reports regarding the effects of bisphosphonates in IJO come from heterogeneous case series in which children with a variety of causes of osteoporosis were included. However, improvements similar to those observed in patients with OI have been noted following bisphosphonate treatment. In one studyreport examining the efficacy of low-dose pamidronate administered in a single day cycle every 3 months to one IJO patient, bone density increased by an average of 20.3% and fracture rates declined dramatically (49). This is essentially identical to the results reported in a different group of 18 subjects with varying forms of osteoporosis (50) In the only other long-term series of 6 90 Pediatric Endocrinology Reviews (PER) n   Volume 3   n   No. 2   n   December 2005 Bisphosphonates in Pediatric Bone Disease  IJO patients, a 1.8-fold increase in lumbar spine BMD z score was observed (63). No deleterious effects on linear growth were apparent with the low-dose regimen. Since spontaneous recovery may occur in IJO patients, it is not possible to accurately assess the efficacy of pamidronate treatment. On the other hand, vertebral fractures may not recover completely without treatment, and one patient developed recurrent bone pain and fractured within a year of stopping clodronate (64). Fibrous dysplasia (FD) : FD is a congenital, but non-inheritable, disorder diagnosed at variable times during childhood and adolescence. FD is associated with activating somatic cell mutations in the gene encoding the alpha subunit of the G stimulatory protein (specifically, heterozygous mutations in codon 201), as are found in McCune-Albright Syndrome (MAS) (65). Such mutations result in high intracellular levels of adenylate cyclase and cAMP. In mesenchymal cells of bone, Table 2: Treatment of Osteogenesis Imperfecta StudyYearnAge(yr)Drug and RouteProtocolDurationBMDOther BoneFractures(per yr)GrowthAdverse Events Bembi199734-8IV pamidronatecalcium and vit D15 mg q 20 d X 1 year, then 30 mg q 20 d (1)30 mg q 20 d (1)15 mg q 20 d x 5 wk, then 15 mg q 10 d22-29 monthsNo Δ (1)-2 SD-nl<-2 SD-nl,81.6% inc3 fx’s during RxNo ΔTransient feverLandsmeer-Beker199731-6PO olpadronatecalcium and vit D5 mg(1), 10 mg (2) per day5-7 yearsIncreased vertebral height6,6,1-2 a, 1-2 p? maybe catch up noneFujiwara199856 avgIV pamidronateAlso PO? (data not given)0.6-1.2 mg/kg q mo6-17 monthsIncreased5.5 a, 2.1 p (ns)No ΔTransient fever and decreased calciumGlorieux1998303-16IV pamidronate6.8 ± 1.1 mg/kg/yr given over 3 days q 4-6 mos1.3-5.0 years41.9 ± 29% increaseDecreased markers BTO2.3 ± 2.2 to 0.6 ± 0.5increased cortical thicknessNo ΔAcute phase reaction in 87%Transient decrease in calcium and phosPlotkin200092.3-20 mosIV pamidronate(6 historical controls)12.4 mg/kg/yr given over 3 days q 1.5-3 mos1 year86-227% increase -6.5 ± 2.1 to -3.0 ± 2.1 SDIncreased vertebral size and cortical thickness2.6 ± 2.5 vs 6.3 ± 1.6 in controlsHeight Z-scores increasedAcute phaseTransient dip in calcium, inc PTH Astrom2002280.6-18IV pamidronate followed by oral alendronate in 5 adolescents after 2-6 yrsVit D10-40 mg/m2 over 5-8 hrs q mo10 mg PO q day2-9 yearsGradual increase in all patientsDecreased markers BTO, increased vertebral heightNo ΔAcute phaseZacharin2002141.4-14IV pamidronateNOTE: no correlation between dis severity, age & response1 mg/kg/d given over 3 days q 4 mos2 years124.7 ± 75.7% increase –SD -5.08 ±1.27 to -3.30 ± 1.71Increased vertebral height, decreased markers (ns)3.4 to 1.5 in 5 ptsAcute phaseNephroclacinosis in 1 pt (thought 2 disease, improved with rx)Banerjee2002101.3-12.7IV pamidronate1 mg/kg/d given over 3 days q 3 mos0.9-3.0 yearsSDS -3.44 to -0.96DecreasedAcute phaseDip in calciumFalk2003622 mos to 14 yrsIV pamidronate1 mg/kg/d given over 3 days q 3.8 mos2 years at least48% mean increase in lumbar spine BMD, 1.0 mean ann incr in z score Decreased in children <3yAcute phaseDip in calciumGandrud200311IV pamidronate1 mg/kg/d once q 3 mos20% mean increase in spinal BMDWith first infusion onlySteelman200318*6 to 21yIV pamidronate30 mg once if <50 kg45 mg once if >50 kg6 mosUp to 33% median increase in spinal BMDN-telopeptides did not correlate with BMDDecreasedNo Δ44% fever22% achesDiMeglio200491-35 mosIV pamidronate1-3 mg/kg divided over 3 days q 4 mos17 mos avg25% mean increase in total body BMDDecreased bone turnover markers 65% decreaseNo ΔTransient feversSakkers2004163-18yPO olpadronate10mg/m2/day2 years0.054 g/cm2 increase in spinal BMD No changes in urinary markers of bone resorption31% decreaseNo ΔNone* Subjects in this trial had “symptomatic osteoporosis,” however, it is not clear that all had OI. 91 Pediatric Endocrinology Reviews (PER) n   Volume 3   n   No. 2   n   December 2005 Bisphosphonates in Pediatric Bone Disease
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