Bisphosphonate Treatment of Pediatric Bone Disease

Transcription

1 Bisphosphonate Treatment of Pediatric Bone Disease 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 1Schneider 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 Corresponding Author: Phyllis W. Speiser, Division of Pediatric Endocrinology, Schneider Children s Hospital, th Ave., New Hyde Park, NY 11040, Phone: , FAX: , pspeiser@lij.edu 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 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 Pediatric Endocrinology Reviews (PER) n Volume 3 n No. 2 n December

2 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, pediatricspecific databases must be employed that provide a z score appropriate for a crosssectional sample of healthy subjects of the same chronologic age. Some investigators O- R O- O = P - C - P = O O- R O- Figure 1: Structure of Bisphosphonate 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. Table 1: Characteristics of Select Bisphosphonates Drug R side chain R side chain Potency Etidronate -OH -CH3 1 Clondronate -Cl -Cl 10 Pamidronate -OH -CH2-CH2-NH2 100 Alendronate -OH -(CH2)3-NH2 500 Ibandronate -OH -CH 2 -CH 2 -N-CH 3 (CH 2 ) 4 -CH Risedronate 2000 Risedronate Sodium C 7 H 10 NO 7 P 2 Na Zoledronate 10,000 Zoledronic Acid C 5 H 10 N 2 O 7 P 2 88 Pediatric Endocrinology Reviews (PER) n Volume 3 n No. 2 n December 2005

3 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. Nitrogencontaining 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 nonhydrolyzable 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 original 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 Pediatric Endocrinology Reviews (PER) n Volume 3 n No. 2 n December

4 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 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

5 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 Study Year n Age (yr) Bembi IV pamidronate calcium and vit D Landsmeer- Beker PO olpadronate calcium and vit D Fujiwara avg IV pamidronate Also PO? (data not given) Drug and Route Protocol Duration BMD Other Bone Fractures (per yr) 15 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 d 5 mg(1), 10 mg (2) per day months mg/kg q mo 6-17 months Glorieux IV pamidronate 6.8 ± 1.1 mg/kg/yr given over 3 days q 4-6 mos Plotkin mos IV pamidronate (6 historical controls) Astrom IV pamidronate followed by oral alendronate in 5 adolescents after 2-6 yrs Vit D Zacharin IV pamidronate NOTE: no correlation between dis severity, age & response Banerjee Falk mos to 14 yrs 12.4 mg/kg/yr given over 3 days q mos mg/m2 over 5-8 hrs q mo 10 mg PO q day 1 mg/kg/d given over 3 days q 4 mos IV pamidronate 1 mg/kg/d given over 3 days q 3 mos IV pamidronate 1 mg/kg/d given over 3 days q 3.8 mos Gandrud IV pamidronate 1 mg/kg/d once q 3 mos Steelman * 6 to 21y IV pamidronate 30 mg once if <50 kg 45 mg once if >50 kg (1) -2 SD-nl <-2 SDnl,81.6% inc 5-7 years Increased vertebral height years 3 fx s during Rx 6,6,1-2 a, 1-2 p Increased 5.5 a, 2.1 p (ns) 41.9 ± 29% increase 1 year % increase -6.5 ± 2.1 to -3.0 ± 2.1 SD 2-9 years Gradual increase in all patients 2 years ± 75.7% increase SD ±1.27 to ± years 2 years at least SDS to % mean increase in lumbar spine BMD, 1.0 mean ann incr in z score 20% mean increase in spinal BMD 6 mos Up to 33% median increase in spinal BMD Decreased markers BTO Increased vertebral size and cortical thickness Decreased markers BTO, increased vertebral height Increased vertebral height, decreased markers (ns) N-telopeptides did not correlate with BMD 2.3 ± 2.2 to 0.6 ± 0.5 increased cortical thickness 2.6 ± 2.5 vs 6.3 ± 1.6 in controls 3.4 to 1.5 in 5 pts Decreased Decreased in children <3y Growth? maybe catch up Height Z-scores increased Adverse Events Transient fever none Transient fever and decreased calcium reaction in 87% Transient decrease in calcium and phos Transient dip in calcium, inc PTH Nephroclacinosis in 1 pt (thought 2 disease, improved with rx) Dip in calcium Dip in calcium With first infusion only Decreased 44% fever 22% aches DiMeglio mos IV pamidronate 1-3 mg/kg divided over 3 days q 4 mos 17 mos avg 25% mean increase in total body BMD Decreased bone turnover markers 65% decrease Transient fevers Sakkers y PO olpadronate 10mg/m2/day 2 years g/cm2 increase in spinal BMD No changes in urinary markers of bone resorption 31% decrease None * Subjects in this trial had symptomatic osteoporosis, however, it is not clear that all had OI. Pediatric Endocrinology Reviews (PER) n Volume 3 n No. 2 n December

6 camp-responsive genes such as c-fos and IL-6 are activated (66), resulting in increased osteoblast recruitment and function and dysplastic bone lesions. Histologically, these lesions appear as irregular bony trabeculae in the marrow space. Radiographically, one observes cysts or lytic lesions with an overall increase in bone width, despite cortical thinning. Bone turnover is elevated, suggesting increased resorptive activity as well as bone formation, and radioisotope uptake is increased on nuclear scans (67). The natural history of FD is variable. Lesions may be asymptomatic and remain stable over long periods, or induce fractures and skeletal deformity (68). Rapidly progressive lesions have been treated with various surgical approaches (69). Treatment efficacy, FD: Recent trials have used intravenous pamidronate to alleviate pain, prevent fractures and decrease markers of metabolic bone turnover in children with MAS and/or FD. In the largest study performed in Canada, the dosage was 0.5 mg/kg for the first day and 1 mg/kg for days 2 and 3 of the first cycle only. Subsequent doses were 1 mg/ kg/day for three day cycles every 4 months and treatment duration ranged from one to nine years. Treatment response could be observed after three days in the first treatment cycle, with decreased bone pain. An asymptomatic decrease in serum calcium, as well as increased PTH, phosphorous, and 1, 25-OH 2 vitamin D concentrations were observed. There were also rapid decreases in serum alkaline phosphatase and urinary n-telopeptides, reflecting decreased bone turnover. Although the gross appearance of lytic lesions did not change, bone mineral content and volumetric bone mineral density increased by 22% above that expected for normally growing children, as measured by DXA (67). In another FD study (70), additional benefits of pamidronate treatment included a dramatic reduction in bone pain and fractures after a single treatment cycle. None of the 13 treated FD patients had any bone pain or recurrence of fractures at the conclusion of follow-up. Except during the first year, treatment was with 1 mg/kg x 3 days every 4 months for 2 to 6 years. A small study of children with McCune-Albright-associated FD from Australia (71) reported reduction in bone pain within the first week of treatment and consequent increased mobility. This protocol differed from the Italian one only by the fact that treatment was every 6 months. Most patients experienced a reduction in fracture incidence. Lumbar BMD improved significantly over the 24 month observation period, with the mean z score increasing from 0.73 to There have been no significant changes in height or weight z-scores in children treated with pamidronate for FD (67). In contrast to the above-cited studies of FD, Collins et. al. (72) assessed skeletal disease burden based on bone scintigraphy in 5 FD patients before and after pamidronate treatment. Whereas pamidronate treatment decreased serum alkaline phosphatase levels, no effect was observed in the skeletal burden score and presumably in functional outcome. Cerebral palsy: Children who are immobilized owing to temporary or permanent disability fail to accrue bone mineral at a normal rate. Among children with cerebral palsy direct correlations exist between the severity of the disability, the child s nutritional status, and bone density. Femoral bone density z-scores decrease with age, despite increases in absolute bone density (73). A single double-blind, placebocontrolled clinical trial has been published examining the safety and efficacy of intravenous pamidronate in treating children with cerebral palsy. The regimen consisted of 3 consecutive days of treatment at 3 monthly intervals for a year. There was a significant increase in bone mineral density z-scores in the distal femur and lumbar spine up to 6 months after the conclusion of the treatment period in the pamidronate group compared to matched controls (74). The latter study did not assess fracture data as proof of efficacy. Less dramatic, but still clinically important, results were reported in other uncontrolled studies of non-ambulatory children subjected to pamidronate treatment at various intervals (75,76). Bisphosphonate safety: Available evidence suggests that bisphosphonates have a good overall safety profile when used in children. reactions such as fever and muscle aches occur with parenteral administration, but gastrointestinal toxicities, headache and/or malaise are more prominent with oral administration (49). A nearly ubiquitous side effect of treatment is a transient acute phase reaction characterized by fever and other flu-like symptoms that occurs within the first 24 hours of the first and/or second at the beginning of the intravenous infusion. Pre-treatment with an antipyretic attenuates this reaction. These symptoms rapidly resolve without further complications (60,70,71). Several children with OI and known respiratory compromise who were treated with pamidronate before 2 years of age developed respiratory distress within the first cycle and required bronchodilation therapy (77). Biochemical changes accompanying bisphosphonate administration include transient decreases in serum calcium and phosphorous, as well as temporary increases in PTH (67,70,78). Although these alterations are rarely clinically significant, they emphasize the importance of ensuring adequate calcium and vitamin D intake during treatment. Bisphosphonates act by interfering with osteoclast-mediated bone resorption, thus altering the balance between bone formation and bone resorption. As a result, a progressive decrease in markers of bone turnover has been observed during the course of treatment. Although a lag in mineralization is observed, there was no evidence of a mineralization defect in any of 45 patient samples analyzed in one study (19) Distinctive radiographic features appear in children receiving bisphosphonates. These consist of metaphyseal bands corresponding to the treatment cycles (79). These bands are a variable mixture of calcified bone and cartilage (80). 92 Pediatric Endocrinology Reviews (PER) n Volume 3 n No. 2 n December 2005

7 Despite a plethora of favorable reports, several cautions exist regarding the widespread use of bisphosphonates in children. As noted above, bisphosphonates theoretically remain in bone indefinitely and the potential effects of these agents on the fetuses of future pregnancies remains to be determined. Two women with OI who had received pamidronate before conception had uneventful pregnancies and delivered infants who also had OI; mothers and children were reported to be free of fractures up to 16 months postpartum (81) Overzealous administration of bisphosphonates has the potential to result in iatrogenic osteopetrosis, as was demonstrated in the case of a 12 year old boy with an unknown metabolic bone disease manifest as bone pain and elevated alkaline phosphatase who received more than quadruple the amount of pamidronate typically used in OI (82). During follow-up of patients with FD treated with bisphosphonates, several required orthopedic surgery for coxa vara (a common complication of FD unrelated to bisphosphonates), two Canadian patients had two fractures each, and five patients had one fracture each (67). There are no apparent changes in fracture healing time, although bone healing is sometimes delayed after surgical osteotomy (83). This study did not specifically track fracture healing time, but rather performed radiographic examination for a visible fracture or osteotomy line one year after the initial event. These observations is could be related to the osteotomy technique used, since other investigators found different results (84) Adults treated mainly with intravenous chronic oral bisphosphonate therapy in the setting of malignancies osteomyelitis have developed unexpected osteonecrosis of the jaw, often following dental surgery (85,86); it is unclear whether the association is causal. The age, duration and optimal dosing regimen of bisphosphonate therapy in children have yet to be established. While some investigators have suggested that early onset of treatment may prevent future problems, no correlation between therapeutic response and disease severity, age, or treatment duration has been reported (46) The harmful effects on linear growth observed in a mouse model of OI (87,88), have not yet materialized in humans, yet potential future adverse effects on growth remain a theoretical concern. Biomechanical studies also showed increased brittleness of bone in alendronate-treated wild-type, but not oim/oim, mice (89). The latter finding has generated some concern regarding potential for deterioration in human bone durability over time due to suppressed bone remodeling following bisphosphonate treatment. Other hypothesized potential adverse effects include rickets, delayed fracture healing, avascular necrosis and teratogenicity (90) At present, there are two ongoing randomized placebocontrolled trials of bisphosphonates in children with severe bone disease owing to OI and IJO. In view of the potential risks, this group of authors believes that until these outstanding questions have been resolved, the use of bisphosphonates should be limited to children with OI, and IJO and cerebral palsy who have severe bone disease as reflected by reduced bone density and frequent fractures. Ideally such patients should be treated in carefully conducted clinical trials with long-term safety monitoring. Future research: As noted above drug efficacy and short term safety over less than a decade have been demonstrated for bisphosphonates. The next challenge is to establish optimal timing and dosing regimens for children with symptomatic osteoporosis. Definitions have yet to be made for grading the severity of bone disease with respect to bone mineral density and fractures. There have been reports citing efficacy of low dose parenteral pamidronate regimens (1 mg/kg once every three months) (49,50). A single short term study in a small group of children with OI showed decreased bone turnover, but no change in fracture rates at one year among children randomised to treatment with either oral alendronate (1 mg/ kg daily) or intravenous pamidronate (3 mg/kg x 3 days every 4 months) (91). The latest generation of bisphosphonates, including zolendronic acid, are 2 to 4 orders of magnitude more potent than earlier formulations such as pamidronate and etidronate, respectively. Although limited experience suggest the newer agents are similar in safety profile to the other drugs (92), this cannot be taken for granted. Given the extended half-life of bisphosphonates in bone, further studies of bone histology in treated children may be helpful in understanding long term safety. As bisphosphonate treatment has become more common in children, investigators have sought to expand the indications for therapy. Among the other conditions in which bisphosphonates appear to produce salutary effects on bone density are idiopathic hyperphosphatasia (93), iatrogenic bone loss with chronic high dose glucocorticoids (94,95) or G-CSF (96), and in anorexia nervosa (97). Additionally, refractory hypercalcemia can be effectively treated with intravenous pamidronate (98,99). Further controlled studies will be needed before bisphosphonate treatment can be considered standard of care for any of these patients. There have been few comparison trials in children to test the relative efficacy of available drugs. In one prospective randomized control trial of patients under 17 years of age who were steroid-dependent following renal transplantation, vitamin D or calcitonin appeared to be at least as effective as oral alendronate (100). Given the good safety profile of vitamin D and calcitonin, these agents, alone or in combination, should be given serious consideration. Finally, new therapeutic agents are introduced continually for treatment of osteoporosis in adults. To date, none of these drugs has been tested in children. At this time, trials with recombinant parathyroid hormone (teriparatide, rhpth [1-34]), an agent that appears to be more effective than Pediatric Endocrinology Reviews (PER) n Volume 3 n No. 2 n December

8 bisphosphonates in actually ameliorating osteoporosis in adults (101), cannot be recommended in children because of animalrat data demonstrating a predisposition to osteosarcoma. It is also difficult to justify using sex hormones or selective estrogen receptor modulators in pre-pubertal individuals. Recommendations: Bisphosphonate therapy for children is still in its infancy. At this time, strong evidence-based recommendations cannot be made, except perhaps for children with osteogenesis imperfecta. Even so, these drugs have entered the clinical practice arena. Larger, carefully controlled, long-term clinical research studies should be conducted before these treatments become standard for the care of children with low bone mineral density and/or frequent fractures. There is also a need for controlled trials to determine appropriate guidelines for conservative management of low bone density in children. The American Academy of Pediatrics has published empiric age-specific guidelines for calcium intake in healthy children (102), however, these guidelines do not address children with low bone density. Nor do the calcium guidelines account for vitamin D intake, weightbearing exercise, or other factors contributing to bone health. Additionally, there are age-specific Recommended Dietary Allowances for vitamin D published by the Institute of Medicine (103), but the adequacy of these vitamin D doses, even for healthy individuals, have been questioned (104). Moreover, even with bisphosphonate therapy, calcium and vitamin D supplementation are required. Clearly, before novel drugs such as bisphosphonates are used in routinely in children, better standards should be established for calcium and vitamin D therapy. There is a similar knowledge gap with respect to the benefits of weight-bearing exercise on bone mineral density. 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Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998;339: Landsmeer-Beker EA, Massa GG, Maaswinkel-Mooy PD, van de Kamp JJ, Papapoulos SE. Treatment of osteogenesis imperfecta with the bisphosphonate olpadronate (dimethylaminohydroxypropylidene bisphosphonate). Eur J Pediatr 1997;156: Plotkin H, Rauch F, Bishop NJ, Montpetit K, Ruck-Gibis J, Travers R, Glorieux FH. Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 2000;85: Zacharin M, Bateman J. Pamidronate treatment of osteogenesis imperfecta--lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and treatment response. J Pediatr Endocrinol Metab 2002;15: Dimeglio LA, Ford L, McClintock C, Peacock M. Intravenous pamidronate treatment of children under 36 months of age with osteogenesis imperfecta. Bone 2004;35: Gordon CM, Bachrach LK, Carpenter TO, Karsenty G, Rauch F. 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