Intravenous Zoledronic Acid Given Every 6 Months in Childhood Osteoporosis

Transcription

1 HORMONE RESEARCH IN PÆDIATRIC S Original Paper Received: March 22, 2013 Accepted: July 5, 2013 Published online: September 18, 2013 Intravenous Zoledronic Acid Given Every 6 Months in Childhood Osteoporosis Hooi Leng Ooi a Julie Briody b Andrew Biggin a Chris T. Cowell a, c Craig F. Munns a, c a Institute of Endocrinology and Diabetes and b Department of Nuclear Medicine, The Children s Hospital at Westmead, and c Discipline of Paediatrics and Child Health, University of Sydney, Sydney, N.S.W., Australia Key Words Zoledronic acid Osteoporosis Children Bisphosphonate Abstract Aim: To evaluate the safety and efficacy of 12 months of zoledronic acid (ZA) administered every 6 months to children with osteoporosis. Methods: Retrospective cohort study of 27 patients (16 male, 11 female) treated with ZA (0.05 mg/ kg/dose) every 6 months for 1 year. 20 were immobile, 4 steroid-induced osteoporosis, 2 idiopathic osteoporosis and 1 neurofibromatosis type had long bone fractures and 12 had vertebral wedging at baseline. Mineral homeostasis, bone mineral density (BMD) and vertebral morphometry were evaluated at baseline and 12 months. Results were compared to published data on 3-monthly ZA treatment. Results: Median age at ZA start was 10.5 years (range ). Following the first infusion, 2 developed asymptomatic hypocalcemic, 14 developed temperature >38 C, 13 aches/pain and 6 nausea. At 12 months, there was reduction in bone turnover and improvement in BMD and vertebral shape. No patient fractured after starting ZA. Growth was normal. Outcomes were similar to 3-monthly ZA. Conclusion: ZA administered 6-monthly was associated with acute phase reaction to the first dose and improvement in BMD, reduction in bone turnover and improved vertebral shape at 12 months. Copyright 2013 S. Karger AG, Basel karger@karger.com S. Karger AG, Basel /13/ $38.00/0 Introduction Childhood osteoporosis can be due to an underlying primary genetic bone disorder or secondary to a chronic medical condition and/or its treatment [1]. There is increasing evidence that intravenous bisphosphonates improve bone mass and density in children with primary and secondary osteoporosis [2, 3]. The majority of studies have been undertaken with intravenous pamidronate in children with osteogenesis imperfecta and have shown improvements in bone mineral density (BMD), vertebral shape, cortical thickness, mobility and height [4 8]. Zoledronic acid (ZA) is a third-generation bisphosphonate with a potency times that of pamidronate [9]. Even though both have a similar mechanism of action [10], ZA has potential advantages over pamidronate in the management of paediatric bone disorders due to its shorter infusion time and longer duration of action. Initially given yearly in adults with osteoporosis, there are data to support third yearly ZA therapy in this population [11]. Due to growth, there is the requirement to treat children more frequently with intravenous bisphosphonates than in adults, as metaphyseal bone made with growth requires dosing with bisphosphonate so as to prevent its resorption [12]. Increasing the interval between infusions in children, so as to minimise the need for repeated cannulation, as well as reduce the cost of therapy, would benefit the children, their families and healthcare Craig Munns Institute of Endocrinology and Diabetes The Children s Hospital at Westmead Locked Bag 4001, NSW 2145 Westmead/Sydney (Australia) health.nsw.gov.au

2 facilities. We had previously reported the effect of 3-monthly ZA, mg/kg, in children with secondary osteoporosis [12]. Here we report the short-term efficacy and safety of 6-monthly ZA, 0.05 mg/kg in childhood secondary osteoporosis. Further studies are required to assess the longerterm outcomes of therapy with regard to reduction of fracture risk and improvement in quality of life. 2 M e t h o d s Patients A retrospective cohort study of 27 patients (16 males and 11 females) with osteoporosis was undertaken. The median age of starting treatment was 10.5 years (range ). Osteoporosis was defined as total BMD (TBMD) and/or lumbar spine areal BMD (LSaBMD) 2.0 standard deviation (SD) with at least one pathological low trauma fracture or bone-related pain [13]. The aetiology of the osteoporosis was: (a) immobility: cerebral palsy (14), myopathy (4), spinal cord injury (1) and lower limb congenital vascular malformation (1); (b) glucocorticoid therapy: Crohn s disease (1), juvenile dermatomyositis (1), liver transplant for endstage liver disease secondary to biliary atresia (1), chronic graftversus-host disease after bone marrow transplant for acute lymphoblastic leukaemia (1); (c) neurofibromatosis type 1 (1), and (d) idiopathic osteoporosis (2). All subjects had at least one low trauma fracture: 16 (59%) had at least one long bone fracture in the previous 12 months and 12 (44.4%) had anterior vertebral wedging with back pain at baseline. Following approval by the Hospital Drug Committee, ZA was administered as part of routine clinical care. Permission to undertake and report this retrospective chart review was obtained from the Human Research Ethics Committee of The Sydney Children s Hospitals Network. Treatment Protocol Intravenous ZA was given at an initial dose of mg/kg with the second dose given 6 weeks later at mg/kg. Following the first infusion, all subjects were supplemented with twicedaily calcium 1,000 mg and calcitriol 0.25 μg for 3 days. All subsequent ZA doses were 0.05 mg/kg given at 6-monthly intervals (0.1 mg/kg/year). The calculated dose of ZA was diluted in 50 ml 0.9% sodium chloride and infused over 30 min. Prior to each dose, postmenarcheal females had a negative urinary pregnancy test. Prior to the start of treatment, all children were assessed by a paediatric endocrinologist and all had serum 25-hydroxyvitamin D (25(OH)D), urea and creatinine concentrations within quoted reference ranges. Children were commenced on cholecalciferol 400 IU/day and prescribed calcium supplementation if their dietary intake was less than the recommended daily intake [ 1]. They were also reviewed by a paediatric dentist before starting treatment and 6-monthly thereafter. An t h ro p o m e t r y Height, weight and calculated body mass index (BMI) SD score were evaluated at baseline and 12 months and converted to agematched SD using the 2000 CDC growth chart data [14]. Pubertal staging was performed at baseline and 12 months using the Tanner method [15]. Biochemistry Measurement Mineral homeostasis was assessed at baseline and 12 months: serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), osteocalcin and 25(OH)D. The plasma calcium level was also measured at the start of treatment and 48 and 72 h after the first infusion. Calcium, phosphate and ALP were measured using a dry chemistry technique (Vitros Fusion 5.1; Ortho-Clinical Diagnostics). PTH was measured by two-site chemiluminescent enzyme-labelled immunometric assay (Immulite; DPC, Los Angeles, Calif., USA). 25(OH)D was measured by radioimmunoassay (DiaSorin, Stillwater, Minn., USA). Osteocalcin was determined using solid-phase chemiluminescent immunoassays (Immulite 1,000; Siemens, Los Angeles, Calif., USA). B o n e D e n s it o m e t r y BMD at baseline and 12 months were determined by DXA using a Lunar Prodigy (GE Lunar Radiation Corp., Madison, Wisc., USA). Subjects were positioned, scanned and analysed according to standard manufacturer recommendations. Measurements were analysed using software version 8.6. Total body and postero-anterior lumbar spine scans were performed on all subjects. These provided TBMD, total body bone mineral content (TBMC), LSaBMD and lumbar spine areal bone mineral content (LSaBMC). The lumbar spine volumetric BMD (LSvBMD) was calculated as per Carter et al. [16] in order to reduce the influence of height on the lumbar spine BMD. The DXA value conversion to age- and heightmatched Z-scores were based on our published normative data [17, 18] using an expanded dataset (n = 650). The TBMC adjusted for lean tissue mass ratio (BMC LTM ), bone mineral content for bone area (BMC BA ), lean tissue mass for height (LTM Ht ) and bone area for height (BA Ht ) were calculated on the basis of our published normative data [19]. These ancillary variables helped to explain the aetiology of BMC and BMD measurement, especially in the paediatric population where both bone and body size change significantly during growth. Vertebral Morphology Using lateral thoraco-lumbar spine radiographs taken at baseline and 12 months, vertebral morphology was assessed by a single observer (H.L.O.). Measurers were made of posterior, middle and anterior vertebral body heights, and expressing these as a ratio of the inferior length of the vertebral body as described previously [8]. Significant vertebral wedging was defined as a greater than 20% decrease in anterior vertebral body height as compared to the posterior height [20]. This technique was used to evaluate the morphological outcome of vertebrae found to have compression at baseline and to assess for new vertebral compression fractures at 12 months. S t a t i s t i c s Data were presented as median with interquartile range (IQR) unless mentioned otherwise. Statistical analyses were performed using SPSS version 19.0 (SPSS, Inc., Chicago, Ill., USA). Wilcoxon s non-parametric paired test was employed to compare various parameters at baseline and 12 months. To allow comparison with previously published ZA data given at a dose of mg/kg 3-monthly [12], we calculated the changes of BMC LTM, TBMD, LSaBMD and LSvBMD age-matched Z-score at baseline and after 12 months of treatment. The changes between the two groups were expressed in mean ± SD as per previous report. The differences at baseline and 12 months in patients treated with Ooi/Briody/Biggin/Cowell/Munns

3 Table 1. Baseline demographic characteristics according to gender All Male Female p value, gender Number Age, years 12.3 ( ) 13.7 ( ) 11.4 ( ) 0.6 Height SD 1.33 ( 2.86 to 0.13) 0.19 ( 2.06 to 0.41) 1.33 ( 3.28 to 0.88) 0.1 Weight SD 1.18 ( 3.15 to 0.38) 0.36 ( 1.47 to 0.86) 1.39 ( 3.58 to 0.87) 0.03 BMI SD 0.50 ( 1.55 to 0.59) 0.03 ( 0.70 to 1.79) 1.02 ( 1.83 to 0.24) 0.02 TBMD (Ht Z-score) 0.56 ( 1.70 to 0.35) 1.18 ( 2.04 to 0.35) 0.52 ( 1.01 to 0.08) 0.2 TBMC (Ht Z-score) 1.82 ( 2.15 to 0.75) 1.89 ( 2.21 to 0.66) 1.88 ( 2.3 to 0.91) 1.0 LSaBMD (Ht Z-score) 1.74 ( 2.43 to 0.96) 1.82 ( 2.25 to 0.53) 1.42 ( 2.66 to 0.82) 0.9 BMC LTM (Z-score) 1.68 ( 2.51 to 0.60) 1.61 ( 2.43 to 0.40) 2.14 ( 2.52 to 0.46) 0.7 Values are median (IQR range). Ht = Height. a 3-monthly regimen and this study were then compared using the Wilcoxon s non-parametric independent t test. All tests were twotailed and p < 0.05 was considered as statistically significant. R e s u l t s Between August 2008 and April 2010, 27 children were started on ZA. Baseline demographic characteristics are shown in table 1. There were no differences by gender except male patients had significantly greater weight and BMI SD. For the comparison between various parameters at baseline and 12 months after treatment, males and females were analysed together. The populations in the two 3- and 6-monthly studies were similar, with the 3-monthly cohort consisting of 20 children (9 males and 11 females) with a mean age of 9.6 ± 4.7 years (range ) [12]. Their underlying diagnoses were: immobility secondary to cerebral palsy (10), steroid-induced osteopenia secondary to chronic inflammatory conditions such as Crohn s disease (4), glycogen storage disease (1), Alagille s syndrome (1), Wilms tumour (1), neurofibromatosis type 1 (1) and idiopathic osteoporosis (2) [12]. The indications for staring ZA therapy were the same for both cohorts [12]. Height, Weight and BMI As a group, growth was normal, with no significant difference seen between the median Z-score at baseline and 12 months for weight [ 1.18 (range 3.15 to 0.38) to 0.78 (range 3.22 to 0.44), p = 0.81], height [ 1.33 (range 2.86 to 0.13) to 1.48 (range 2.89 to 0.01), p = 0.74] and BMI [ 0.50 (range 1.55 to 0.59) to 0.60 (range 2.10 to 0.72), p = 0.94]. Six-Monthly Zoledronic Acid in Children Table 2. Mineral homeostasis at baseline and 12 months after treatment with ZA Reference range Bio ch e mi s t r y There were significant reductions seen from baseline to 12 months post-treatment in the phosphate, ALP and osteocalcin, while other biochemical parameters remained stable ( table 2 ). In the 3-monthly ZA study, ALP and osteocalcin were reduced at 12 months, but phosphate level remained stable [12]. DXA Scanning Due to the significant reduction in height of the cohort, the primary DXA analysis was performed using height-adjusted Z-scores. All parameters measured demonstrated significant increase at 12 months post-treatment compared to baseline ( table 3 ). The LSaBMD, LSvBMD and BMCLTM showed the most significant increase. To allow comparison between our previously Baseline 12 months p value Calcium, mmol/l ( ) 2.36 ( ) 0.2 Phosphate, mmol/l ( ) 1.41 ( ) 0.03 ALP, U/l ( ) 148 ( ) 0.01 PTH, pmol/l ( ) 3.7 ( ) 0.2 Osteocalcin, nmol/l ( ) 2.4 ( ) < (OH)D, nmol/l >50 75 (67 94) 78 (58 86) 0.3 Values are median (IQR). 3

4 Age Z-score p = 0.5 p = Monthly regimen, n = 20 6-Monthly regimen, n = 27 p = 0.1 p = 0.3 Vertebral height ratio ** ** ** BMC LTM TBMD LSaBMD LSvBMD Anterior Middle Baseline 12 months Posterior Fig. 1. Twelve-month bone densitometry parameters in children treated with ZA mg/kg 3-monthly [12] and 0.05 mg/kg 6-monthly. Fig. 2. Vertebral morphology showing median anterior, middle and posterior vertebral height ratio in 12 patients with anterior wedging at baseline. All height ratios improved significantly at 12 months after treatment with ZA. * * p = Table 3. Bone mineral densitometry data at baseline and 12 months after treatment with ZA Baseline 12 months p value TBMD (Ht Z-score) 0.56 ( 1.70 to 0.35) 0.03 ( 1.20 to 0.82) 0.03 TBMC (Ht Z-score) 1.82 ( 2.15 to 0.75) 1.46 ( 1.89 to 0.50) LSaBMD (Ht Z-score) 1.74 ( 2.43 to 0.96) 0.37 ( 1.37 to 0.09) <0.001 LSaBMC (Ht Z-score) 0.71 ( 1.32 to 0.02) 0.16 ( 1.01 to 0.73) LSvBMD (Ht Z-score) 1.36 ( 1.70 to 0.04) 0.10 ( 0.83 to 1.10) <0.001 BMC LTM (Z-score) 1.68 ( 2.51 to 0.60) 0.10 ( 0.84 to 1.20) <0.001 BMC BA (Z-score) 0.03 ( 0.85 to 1.45) 0.40 ( 0.49 to 1.41) 0.04 LTM Ht (Z-score) 0.54 ( 1.36 to 0.20) 0.61 ( 2.11 to 0.05) 0.01 BA Ht (Z-score) 2.37 ( 3.31 to 0.83) 1.69 ( 2.87 to 0.04) Values are median (IQR). Ht = Height. published 3-monthly treatment regimen [12], agematched Z-scores were calculated for BMC LTM, TBMD, LSaBMD and LSvBMD. There were no statistically significant differences in the improvement observed between the two different regimens ( fig. 1 ). Vertebral Morphology Twelve (44%) showed evidence of anterior vertebral wedge deformity at baseline. Vertebral morphology on affected vertebrae showed a significant improvement in all the anterior, middle and posterior vertebral height ratios after 12 months of treatment, leading to improved 4 vertebral shape ( fig. 2 ). Although not formally assessed, the 12 children with vertebral compression reported an improvement in back pain. Adverse Effects of Treatment Following the first infusion, 2 (7.4%) and 1 (3.7%) developed asymptomatic hypocalcaemia (serum calcium <2.10 mmol/l) at 48 and 72 h respectively, 14 (52%) developed temperature >38 C, 13 (48%) complained of muscle aches/pain, and 6 (22%) had nausea. These are comparable to the symptoms experienced following first infusion of the 3-monthly ZA protocol [12]. No other ad- Ooi/Briody/Biggin/Cowell/Munns

5 verse effects were noted. Regular dental examination revealed no cases of osteonecrosis of the jaw. One patient sustained two hand fractures following significant trauma while on treatment. There were no new long bones or vertebral fractures during the treatment period. D i s c u s s i o n This is the first report of 12-month outcome data in children with secondary osteoporosis who have been treated with ZA at 6-monthly intervals. Despite a relatively small and heterogeneous cohort of 27 children with and reporting 12-month treatment data, there was a significant reduction in bone turnover and improvement in bone mass, BMD and vertebral deformity. There were no new low trauma long bone or vertebral fractures following the start of treatment, however 12 months may be too short a period over which to assess the effect of treatment on fracture prevention. A similar ZA treatment regimen in children with osteogenesis imperfecta showed improvement in bone density comparable to pamidronate therapy [21]. Bone age was not routinely evaluated in this cohort. Some authors have used bone age as an approach to adjust growth and puberty [22]. The assessment of bone age can be unreliable and significant delay (>2 years) is required before it begins to influence BMD results [23]. The improvements in BMC LTM, TBMD, LSaBMD, LSvBMD and vertebral morphology at 12 months were comparable to patients treated with a previously reported 3-monthly ZA regimen [12]. These findings suggest that 6-monthly ZA with an annualised dose of 0.1 mg/kg is effective in childhood osteoporosis. This raises the issue of what is the optimal dosing interval for ZA in children and could the dosing interval be increased further without attenuating its efficacy? In growing children, each bisphosphonate treatment cycle leads to the accumulation of a thin band of mineralised tissue at the interface between growth plate and metaphysis which is evident as metaphyseal lines on the radiographs [24]. This represents persistent calcified cartilage in the horizontal trabeculae which later remodels into secondary bone [24]. In children with osteogenesis imperfecta who were treated with a 4-monthly pamidronate regimen, bone resorption increased after treatment was discontinued for 2 years but remained significantly lower than in untreated patients [25]. BMC continued to increase but LSaBMD Z-score decreased as the gain in LSaBMD was reduced compared to that of healthy subjects [25]. The effects of treatment discontinuation were more pronounced Six-Monthly Zoledronic Acid in Children in growing children than in those who had achieved final height. This was clearly illustrated by Rauch et al. [26] where the radial metaphyseal BMC Z-score reduced by 2 SD or more in growing children after treatment discontinuation whereas no patients with closed growth plate experienced a decrease by more than 2 SD at 1.9 years. Following treatment discontinuation, the new bone laid down would have fragility similar to that of bisphosphonate-naive bone. The interface between this weaker bone and stronger bisphosphonate-treated bone could represent a stress-riser and site for potential fracture. The same would hold for a treatment regimen with a prolonged interval between doses. Compared to our previous series of children treated with ZA mg/kg 3-monthly [12], those treated with the 6-monthly regimen had similar clinical outcomes with increase in BMD and reduction in serum markers of bone turnover. In osteoporotic post-menopausal women, intravenous ZA 5 mg annually appeared to have beneficial effects up to 36 months [11]. However, it is unlikely that such a regimen will be effective in the growing child. Despite proven efficacy in clinical trials and an increasing number of case series, there remains ongoing safety concerns of bisphosphonate administration in children. Children should therefore receive therapy under the supervision of centres experienced with their use [27]. Oversuppression of bone remodelling [28] with the development of an osteopetrosis-like bone phenotype has been reported following a very high dose of pamidronate given in one child [29]. There continues to be no reports of osteonecrosis of the jaw in children treated with bisphosphonates [30]. Despite this, ongoing surveillance and the maintenance of excellent oral hygiene are recommended. It is well recognised that bisphosphonates cross the placenta and are contraindicated during pregnancy. With their long half-life, there is also concern about the recirculation of bisphosphonates with bone remodelling and the potential for this to cross the placenta many years after the stopping of treatment. The potential concentration of bisphosphonate from this scenario is likely to be very small and there are yet to be any reports of adverse foetal outcome [31]. In conclusion, this report highlights the potential efficacy of 6-monthly ZA 0.05 mg/kg in childhood osteoporosis with an increase in BMD and improvement in vertebral shape. Apart from acute phase reaction to the first dose, ZA was well tolerated with no significant adverse events. The clinical benefit of ZA of increasing BMD on reducing fracture rate and improving vertebral shape in children with secondary osteoporosis remain to be deter- 5

6 mined. Data from this report provide valuable information around which further large prospective intervention trials can be based. Not until such studies are performed can this treatment regimen be widely recommended. Acknowledgements This research was approved by the Sydney Children s Hospitals Network Human Research Ethics Committee. We would like to thank Mary McQuade, Clinical Nurse Consultant for Bone Health, for administration and patient care and the staff in Clinical Biochemistry, Medical Imaging and Nuclear Medicine Departments for performing the measurements. Disclosure Statement C.F.M. received zoledronic acid from Novartis for an investigator-initiated clinical trial. References 1 Munns CF, Cowell CT: Prevention and treatment of osteoporosis in chronically ill children. J Musculoskelet Neuronal Interact 2005; 5: Bachrach LK, Ward LM: Clinical review: bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab 2009; 94: Ward L, Tricco A, Phuong PN, et al: Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Cochrane Database Syst Rev 2007; 4:CD Glorieux FH: Experience with bisphosphonates in osteogenesis imperfecta. Pediatrics 2007; 119:S163 S Rauch F, Travers R, Plotkin H, et al: The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 2002; 110: Rauch F, Glorieux FH: Osteogenesis imperfecta. Lancet 2004; 363: Rauch F, Plotkin H, Zeitlin L, et al: Bone mass, size and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy. J Bone Miner Res 2003; 18: Land C, Rauch F, Munns CF, et al: Vertebral morphology in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate treatment. Bone 2006; 39: Fleisch H: Bisphosphonates in Bone Disease: From the Laboratory to the Patient, ed 4. San Diego, Academic Press, Brown JJ, Zacharin MR: Safety and efficacy of intravenous zoledronic acid in paediatric osteoporosis. J Pediatr Endocrinol Metab 2009; 22: Grey A, Bolland M, Wattie D, et al: Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J Bone Miner Res 2010; 25: Simm PJ, Johannesen J, Briody J, et al: Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis. Bone 2011; 49: Baim S, Leonard MB, Bianchi ML, et al: Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Pediatric Position Development Conference. J Clin Densitom 2008; 11: Kuczmarski RJ, Ogden CL, Guo SS, et al: 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat ; 246: Tanner JM: Growth at Adolescence, ed 2. Oxford, Blackwell Scientific, Carter DR, Bouxsein ML, Marcus R: New approaches for interpreting projected bone densitometry data. J Bone Miner Res 1992; 7: Lu PW, Briody JN, Ogle GD, et al: Bone mineral density of total body, spine, and femoral neck in children and young adults: a crosssectional and longitudinal study. J Bone Miner Res 1994; 9: Ogle GD, Allen JR, Humphries IR, et al: Bodycomposition assessment by dual-energy x-ray absorptiometry in subjects aged 4 26 years. Am J Clin Nutr 1995; 61: Högler W, Briody J, Woodhead HJ, et al: Importance of lean mass in the interpretation of total body densitometry in children and adolescents. J Pediatr 2003; 143: Genant HK, Wu CY, van Kuijk C, et al: Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 1993; 8: Vuorimies I, Toiviainen-Salo S, Hero M, et al: Zoledronic acid treatment in children with osteogenesis imperfecta. 2011; 75: Gordon CM, Bachrach LK, Carpenter TO, et al: Duel energy x-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom 2008; 11: Grissom LE, Harcke HT: Radiographic features of bisphosphonate therapy in pediatric patients. Pediatr Radiol 2003; 33: Rauch F, Travers R, Munns C, et al: Sclerotic metaphyseal lines in a child treated with pamidronate: histomorphometric analysis. J Bone Miner Res 2004; 19: Rauch F, Munns C, Land C, et al: Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab 2006; 91: Rauch F, Cornibert S, Cheung M, et al: Longbone changes after pamidronate discontinuation in children adolescents with osteogenesis imperfecta. Bone 2007; 40: Simmons JH, Zeitler PS: Osteopenia in pediatric patients: when and how to intervene. Curr Opin Endocrinol Diabetes 2006; 13: Marini JC: Bone: Use of bisphosphonates in children-proceed with caution. Nat Rev Endocrinol 2009; 5: Whyte MP, Wenkert D, Clements KL, et al: Bisphosphonate-induced osteopetrosis. N Engl J Med 2003; 349: Brown JJ, Ramalingam L, Zacharin MR: Bisphosphonate-associated osteonecrosis of the jaw: does it occur in children? Clin Endocrinol 2008; 68: Munns CF, Rauch F, Ward L, et al: Maternal and fetal outcome after long-term pamidronate treatment before conception: a report of two cases. J Bone Miner Res 2004; 19: Ooi/Briody/Biggin/Cowell/Munns