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Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis
Bone 49 (2011) 939–943
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Bone j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b o n e
Original Full Length Article
Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis Peter J. Simm a,⁎, Jesper Johannesen a, Julie Briody c, Mary McQuade a, Brian Hsu d, Corinne Bridge d, David G. Little b, d, Christopher T. Cowell a, b, Craig F. Munns a, b a
Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia Department of Paediatrics and Child Health, University of Sydney, Sydney, Australia c Department of Nuclear Medicine, The Children's Hospital at Westmead, Sydney, Australia d Department of Orthopaedic Surgery, The Children's Hospital at Westmead, Sydney, Australia b
a r t i c l e
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Article history: Received 10 March 2011 Revised 16 June 2011 Accepted 19 July 2011 Available online 28 July 2011 Edited by: Robert Recker Keywords: Osteopenia Bone fragility Bisphosphonates Zoledronic acid Fracture
a b s t r a c t There are limited data on the use of bisphosphonate therapy for secondary osteoporoses in childhood, and no previous reports of the use of zoledronic acid in this group. We report 20 children with a variety of underlying primary diagnoses with associated secondary osteoporosis, who were treated with 3 monthly zoledronic acid for 2 years (annualised dose 0.1 mg/kg/year). There was a significant improvement in lumbar spine (by 1.88 SD ± 1.24 over first 12 months, p b 0.001) and total bone mineral density as assessed by dual energy absorptiometry (DXA) scans, with a similar increase in bone mineral content for lean tissue mass (mean increase 1.34 SD in first 12 months, p b 0.001). Bone turnover was reduced with a suppression of both osteocalcin and alkaline phosphatase in the first 12 months of treatment. Skeletal architecture was improved, with increased second metacarpal cortical thickness from 2.44 mm to 2.72 mm (p b 0.001) and improved vertebral morphometry, with 7 patients who had vertebral wedging at baseline showing improved anterior (p = 0.017) and middle (p = 0.001) vertebral height ratios. Aside from well reported transient side effects with the first dose, there were no adverse effects reported. No adverse effects on anthropometric parameters were seen over the course of the study. Despite all patients having sustained fragility fractures prior to treatment, no fractures were reported during the study period. Further evidence is required to confirm efficacy, with long term follow up required to assess the impact of treatment on fracture risk. Crown Copyright © 2011 Published by Elsevier Inc. All rights reserved.
Introduction Childhood and adolescence are critical periods for optimising bone strength, which is itself determined by bone size, geometry, quality, and mass — variables that are influenced by genetic factors, physical activity, nutrition and hormones [1]. For children with genetic skeletal disorders or chronic disease, bone strength is often compromised increasing the lifetime risk of osteoporosis [1]. In children with chronic illnesses the increased risk of fragility fracture are predominantly due to two factors. Firstly, there is the impact of the underlying condition (for example reduced mobility or poor nutrition) on skeletal development and secondly, the negative effect on bone mass accrual of medications (for example glucocorticoids) used to treat the chronic illness [2]. The incidence of vitamin D deficiency is also increased in children with chronic disease, which can have a negative effect on bone development. ⁎ Corresponding author at: The Children's Hospital at Westmead, Institute of Endocrinology and Diabetes, Westmead NSW 2145, Australia. Fax: + 61 2 9845 3170. E-mail address: [email protected] (P.J. Simm).
The clinician is therefore required to identify children at greatest risk for future fragility fracture based on these potential risk factors. Dual energy x-ray absorptiometry (DXA) is a frequently used measure of bone mass and density. Recent data showing an association between low bone density as assessed by DXA and fractures in children [3], would support its use to monitor for children at risk of fragility fracture and follow treatment aimed at reducing fracture risk. Radiographs for vertebral morphometry and second metacarpal cortical thickness can also be used to assess bone development in children [1]. When used in conjunction with DXA, these radiological evaluations can give a greater understanding of the state of bone health and effect of treatment. Bisphosphonates are being administered with increasing frequency to children with secondary osteoporosis, however, the efficacy and safety of these agents require further clarification. A Cochrane review found only four randomised controlled trials (RCT) of significant use of bisphosphonates in children and adolescents with secondary osteoporosis [4–7]. The numbers in each study were small (6–20 patients in the treatment arm) and follow-up short (12 months in
8756-3282/$ – see front matter. Crown Copyright © 2011 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2011.07.031
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each study). While all of these trials showed within-group benefit in improved bone mineral density, only one clearly showed a betweengroup benefit [7]. None of these studies used zoledronic acid. To date a small number of studies have been published using longer term zoledronic acid in paediatric patients with primary osteoporoses such as osteogenesis imperfecta [8–10]. A single dose of Zoledronic acid has also been shown to improve bone density in children with Crohn's disease [11]. Zoledronic acid has also been trialled for management of skeletal metastases in paediatric cancer patients, with no reports of significant adverse events [12]. A review of interventions for bone health in cerebral palsy found only 3 studies using bisphosphonates, none of which was using zoledronic acid [13]. No study has looked at the long term effects of zoledronic acid in secondary osteoporoses and there have been no studies powered to assess fracture rate reduction. Despite the growing use of bisphosphonates in children and adolescents for an increasing variety of conditions, long term studies are still required to fully address issues of safety and efficacy [14]. This case-series reports 20 children with secondary osteoporosis, defined as total body BMD (TBMD) and/or lumbar spine BMD (LSBMD) z-score b −2.0 and at least one pathological low trauma fracture or bone pain, treated with zoledronic acid for an average of 1.24 years and followed for 2 years after initiation of treatment. Material and methods Subjects 20 children (9 males and 11 females) with a mean age of 9.6 ± 4.7 years (range: 3.3–16.5 years), were diagnosed with secondary osteoporosis defined as TBMD and/or LSBMDb −2.0 and at least one pathological low trauma fracture or bone related pain [15]. Their underlying diagnoses were: immobility secondary to cerebral palsy (10 patients), 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 osteopenia/osteoporosis of unknown origin [2]. Following approval by the Hospital Drug Committee zoledronic acid was administered as part of our routine care. Permission to undertake and report this retrospective chart review was obtained from the Institutional Ethics Committee. Treatment protocol Intravenous zoledronic acid was given at an initial dose of 0.0125 mg/kg with the second dose given 12 weeks later at 0.025 mg/kg. All subsequent doses were 0.025 mg/kg given at 12 weekly intervals. The calculated dose of zoledronic acid was diluted in 50 ml 0.9% NaCl and infused over 30 min. The annualised dose was 0.10 ± 0.02 mg/kg given over a period of 1.7 ± 0.7 years (range: 0.5– 2 years). Prior to the start of treatment, all children were assessed by a paediatric endocrinologist and all had serum 25-hydroxyvitamin D, urea and creatinine concentrations within quoted reference ranges and normal renal ultrasound scans. Children were commenced on a multivitamin containing 400 IU vitamin D per day and prescribed calcium supplementation if their dietary intake was less than the recommended daily intake [1]. Anthropometry, blood analysis and DXA scans Height, weight and calculated body mass index (BMI) standard deviation score (SD) as well as mineral homeostasis were evaluated at baseline, 1 and 2 years: calcium (Ca), phosphorus (Pi), parathyroid hormone (PTH), alkaline phosphate (ALP), osteocalcin (OST) and 25-hydroxyvitamin D (25-OHD). A SAS programme that applies the 2000 CDC growth chart data was used to calculate anthropometric SD
[16]. (http://www.cdc.gov/growthcharts/computer_programs.htm). Ca, Pi 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, California, USA). 25-OHD was measured by radioimmunoassay (Diasorin, Stillwater, Minn, USA). OST was determined using solid phase chemiluminescent immunoassays (Immulite 1000, Siemens, Los Angeles, USA). Bone mineral density (BMD) at baseline, 1 and 2 years was determined by DXA using a Lunar Prodigy (GE Lunar Radiation Corp, Madison, Wisconsin, USA). Subjects were positioned, scanned and analysed according to standard manufacturer recommendations. Measurements were analysed using software version 8.10. Total body, postero-anterior lumbar spine and proximal femur scans were performed on all subjects. These provided total bone mineral density, adjusted for age (TBMD), lumbar spine bone mineral density (LSBMD), total bone mineral content (TBMC), and total bone mineral content adjusted for lean tissue mass ratio (BMCLTM).The volumetric LSBMD was calculated as per Carter et al. [17], in order to reduce the influence of height on the LSBMD. The DXA value conversion to age, height and sex-matched SD-scores (Z-scores) were based on previously published CHW normative data [18,19] using an expanded dataset (n= 650) and updated software version 4.7. The BMCLTM was calculated on the basis of previously published CHW normative data [20]. These ancillary variables help explain the aetiology of the BMC and BMD measurements, especially in the paediatric population when both bone and body size change dramatically during growth. Postero-anterior radiographs of the left hand at baseline and 1 year were evaluated by paediatric radiologists to calculate bone age as per Greulich et al. [21]. Metacarpal cortical thickness was measured on the bone age X-ray at the midpoint of the 2nd metacarpal (using Magicweb software, Visage Imaging, Inc, Andover MA). Metacarpal cortical area was calculated by estimating the total area using the total diameter of the bone, and subtracting the medullary area, calculated by measuring the internal diameter. Lateral thoraco-lumbar spine radiographs were taken at baseline, 1 and 2 years. These were assessed for spondylolisthesis and vertebral morphology. Morphology was determined by measuring the posterior, mid-body and anterior vertebral body height, and expressing these as a ratio of the inferior length of the vertebral body as described previously [22]. Significant vertebral wedging was defined as a greater than 15% decrease in anterior vertebral body height as compared to the posterior height [23]. Statistical analysis Means and standard deviations are reported for all data. Data was assessed for normality. Student t-test was used comparing groups at entry. Repeated measurement was used analysing data over the 2 years follow-up. For data that was not normally distributed Wilcoxon's non-parametric paired test was employed. A p-value of b0.05 was selected as the level of significance for this study before the data analysis. Results Baseline anthropometry characteristics for height, weight and BMI are shown in Table 1. No difference between genders was observed. Baseline TBMD, LSBMD, TBMC and BMCLTM measured by DXA are also found in Table 1, with again no gender difference observed. Height, weight, BMI and bone age No significant difference was seen in height, with the mean Z score at baseline − 1.58, compared with −2.06 at 24 months, (p = 0.17).
P.J. Simm et al. / Bone 49 (2011) 939–943
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5
Table 1 Baseline demographics according to gender.
***
4
Gender
All
Male
Female
N
20
9
11
Age (year) Height SD Weight SD BMI SD TBMD (z-score) Areal LSBMD (z-score) TBMC (z-score) BMC_LTM (z-score)
9.6 ± 4.7 − 1.6 ± 2.0 − 1.8 ± 1.8 − 12 ± 2.8 − 1.5 ± 1.6 − 2.7 ± 1.4 − 1.9 ± 1.3 − 0.7 ± 3.4
10.2 ± 4.4 − 1.4 ± 1.4 − 1.6 ± 1.8 − 0.9 ± 2.2 − 1.5 ± 1.5 − 2.1 ± 1.5 − 1.5 ± 0.8 − 1.0 ± 3.6
9.1 ± 5.1 − 1.7 ± 2.4 − 2.0 ± 1.9 − 1.3 ± 3.2 − 1.5 ± 1.8 − 3.3 ± 1.2 − 2.3 ± 1.6 − 0.5 ± 3.3
3
p-Value, gender
*
2 1 Z score 0 (SD) -1
0.61 0.41 0.82 0.75 0.99 0.07 0.26 0.79
-2 -3 -4 -5
***
*
(a)
(b)
(c)
(d)
0 months 12 months 24 months
Legend: mean ± SD.
Similarly, no significant change was seen in weight or BMI SD from baseline to 2 years (data not shown). Bone age increased in accordance with chronological age from pre treatment (9.3 ± 5.0) and at 2 years 11.0 ± 5.0 (p = 0.91). Background fracture history The mean number of fractures sustained prior to commencing the study was 1.7 (range 1–6). 6 patients had sustained vertebral fracture(s) alone, 12 had sustained long bone fracture(s) and 2 had sustained both long bone and vertebral fracture(s). No fractures were recorded in the 20 subjects during the study period. Biochemistry There were significant reductions seen from baseline to 1 year post treatment in the bone turnover markers alkaline phosphatase and osteocalcin, while other biochemical parameters remained stable (Table 2). DXA scanning A significant increase was demonstrated in total BMD Z scores (mean − 1.51 ± 1.59 at baseline to − 1.04 ± 1.51 at 24 months, p = 0.04) and lumbar spine BMD Z scores (− 2.72 ± 1.4 at baseline to −0.46 ±1.47 at 24 months, p b 0.001). Similarly, there was a marked increase in the BMCLTM Z-score (−0.72± 3.27 at baseline to 1.39± 2.64 at 24 months, p b 0.001) (Figs. 1a–c). The volumetric age adjusted LSBMD Z-score also increased over the 2 year period (mean −1.84, ±1.01 at baseline to 0.42, ±1.97 at 24 months, p = 0.02) (Fig. 1d). The greatest increase in LSBMD Z-score occurred during the first year of treatment with an increase of 1.88 ± 1.24 and 0.38 ± 0.70 (p b 0.001) over the 1st and 2nd year periods respectively. A similar trend was seen for volumetric LSBMD Z-score, with an increase of 1.57 ± 1.07 and 0.69 ± 1.47 (p = 0.08) over the 1st and 2nd year periods respectively. Metacarpal/vertebral morphometry from plain X-rays Metacarpal parameters were available in 12 patients, with pretreatment films compared with post-treatment (median 27 months
Fig. 1. DXA scan results for patients with secondary osteoporosis treated with zoledronic acid showing improvement in all measures over the course of the study. (a) total body areal bone mineral density Z scores, (b) lumbar spine areal bone mineral density Z scores, (c) bone mineral content for lean tissue mass Z scores, and (d) lumbar spine volumetric bone mineral density Z scores. * represents p b 0.05, *** represents p b 0.001 (baseline compared with 24 month results).
post commencement of ZA). Mean cortical thickness increased from 2.44 mm to 2.72 mm (p b 0.001), while mean cortical area increased from 60.19 mm 2 to 70.18 mm 2 (p b 0.001) (Fig. 2). Spine X-rays were available pre treatment for 12 patients, with 7 showing evidence of anterior vertebral wedging or crush fractures prior to the commencement of bisphosphonate treatment. Vertebral morphometry on affected vertebrae in these 7 patients showed a significant improvement in both anterior and middle vertebral height ratios after 2 years of treatment, leading to improved vertebral shape (Fig. 3). Adverse effects of treatment Aside from transient first dose side effects which have been described previously in the Children's Hospital at Westmead cohort [24] no adverse effects were noted, with ongoing dental review revealing no cases of osteonecrosis of the jaw. There were no fractures or spondylolistheses during the treatment or follow-up periods. All patients had serum calcium levels checked 48–72 h after their first infusion, with no significant hypocalcaemia seen. Each patient was treated with supplemental calcium and calcitriol for 3–7 days following the first infusion and Vitamin D sufficiency was maintained throughout the study. Discussion This is the first report of 24 month follow-up zoledronic acid therapy data in children with secondary osteoporosis. Short-term zoledronic acid therapy was safe and associated with increased BMD (especially in the lumbar spine) and cortical thickness. This change was consistent with a real increase in bone mass accrual, as there was no significant change in height Z score and bone age progressed at the expected rate, meaning that accelerated maturation was not driving the observed increase in BMD. Importantly, there was also evidence of
Table 2 Biochemical values over 2 years of zoledronic acid treatment (values reported as mean ± SD) NS: not significant — p N 0.05.
Calcium (mmol/L) Phosphate (mmol/L) Alkaline phosphatase (U/L) Parathyroid hormone (pmol/L) Osteocalcin (nmol/L)
Baseline
1 year
2 years
p Value (1st year vs baseline)
2.34 ± 0.11 1.35 ± 0.23 236.9 ± 179.29 4.3 ± 2.66 7.5 ± 5.04
2.39 ± 0.11 1.41 ± 0.29 185.5 ± 134.65 4.0 ± 2.58 3.9 ± 2.33
2.36 ± 0.14 1.39 ± 0.17 205.13 ± 177.29 4.5 ± 3.35 4.7 ± 3.42
NS NS 0.006 NS 0.026
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Periosteal diameter Endocortical diameter
Fig. 2. Representative patient pre-treatment X-ray of second metacarpal (left) and post treatment X-ray (right) demonstrating increased cortical thickness. Across all subjects, mean cortical thickness increased from 2.44 mm to 2.72 mm (p b 0.001).
vertebral modelling. These data would be in keeping with an increase in bone strength. Growth was not affected by zoledronic acid and as expected, bone turnover was reduced as evidence by the reduction in ALP and osteocalcin. The greatest increase was seen in the first 12 months after commencing therapy, with the majority of children demonstrating normalisation of lumbar spine z-scores (areal and volumetric) after 2 years of treatment. Further data are required to determine the optimal treatment thereafter, but bisphosphonate therapy may then be able to be ceased or continued at a reduced dose. The improved spinal shape is also consistent with previous reports in osteogenesis imperfecta [22] and chronic recurrent multifocal osteomyelitis [25], which further supports the importance of bisphosphonate treatment in young people with vertebral wedging or crushing. Bisphosphonate treatment outcome data from adult studies, and those in children with osteogenesis imperfecta, are important guides in developing the optimal treatment regimen for children with secondary osteoporosis. The best treatment regimen, in terms of choice of drug, route of administration, dosing schedule and treatment duration, remains to be determined and large controlled trails are required. While 3 monthly treatment gave good response in
Fig. 3. Vertebral morphometry — figure depicts a representation of the average ratios of posterior height, mid height and anterior height of vertebral bodies showing anterior wedging or crush fractures in 7 patients. Pre treatment ratios are compared with those seen after 2 years of treatment. There has been a significant increase in mid height ratio (p = 0.017, represented by *) and anterior height ratio (p = 0.001, represented by **).
this study, it may be possible to get similar results if the zoledronic acid was administered less frequently, for example 6 monthly. It is unlikely that extending beyond 6 months would be possible due to the requirement to dose new bone formed with growth and the aim to influence bone modelling as well as remodelling in children. This is evident by the improvement in vertebral shape that is possible in children compared to adults. In children with secondary osteoporosis the importance of other management aspects of bone health should not be forgotten. These include maximising physical activity, ensuring timely pubertal progression, providing adequate intake of calcium and vitamin D and minimising exposure to osteotoxic medication [1]. Ensuring a safe home and school environment so as to limit the risk of accidental trauma is also of great importance. When combined with an effective bisphosphonate regime, best outcomes are likely. Despite evidence of efficacy in a number of clinical contexts in paediatrics, there are still some concerns about the safety of bisphosphonate therapy in children [26,27]. There are a number of recognised side-effects including first dose effects of hypocalcaemia and an acute ‘flu-like’ reaction (as discussed above) [24], with disturbed metaphyseal modelling [28], reduced bone turnover [29] and persistence of calcified cartilage in the metaphysis [30]. Given the long half life in the skeleton, there is also a potential effect on the developing foetus if the mother has been previously treated with these agents [31]. Bisphosphonate-related osteonecrosis of the jaw is well described in adult patients however, there are no reported cases in paediatric patients [32]. Due to these concerns, and the need for paediatric patients to be carefully monitored for such side effects, the use of bisphosphonates in paediatrics should be restricted to centres with experience in the use of this therapy in childhood. In conclusion, our study highlights that zoledronic acid is an effective agent in young people with secondary osteoporosis, with a wide range of primary diagnoses, in causing an improvement in bone density. Zoledronic acid also improved bony architecture with increased metacarpal thickness and reconstitution of vertebral shape seen in these patients. The treatment was well tolerated with no significant side effects. Longer term studies with a larger patient group are required to address the issue of whether improving bone density leads to a long term reduction in fracture risk, but the absence of fractures in a 2 year period in this group, all of whom had previous fragility fractures, is reassuring. Treatment that can reduce morbidity in this patient group that already experience significant burden from their underlying disorders should be strongly considered when appropriate.
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Competing interests Dr. David Little: Novartis, Grant/Research Support; Stryker Biotech, Grant/Research Support, Speakers Bureau. Dr. Jesper Johannesen is a recipient of an unrestricted educational grant from Novonordisk. Ethical approval Approval to perform this research was granted by the Ethics committee of the Children's Hospital at Westmead. References [1] Munns CF, Cowell CT. Prevention and treatment of osteoporosis in chronically ill children. J Musculoskelet Neuronal Interact Jul-Sep 2005;5(3):262–72. [2] Ward L, Tricco AC, Phuong P, Cranney A, Barrowman N, Gaboury I, et al. Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Cochrane Database Syst Rev (Online) 2007(4):CD005324. [3] Clark EM, Tobias JH, Ness AR. Association between bone density and fractures in children: a systematic review and meta-analysis. Pediatrics Feb 2006;117(2): e291–7. [4] Henderson RC, Lark RK, Kecskemethy HH, Miller F, Harcke HT, Bachrach SJ. Bisphosphonates to treat osteopenia in children with quadriplegic cerebral palsy: a randomized, placebo-controlled clinical trial. J Pediatr Nov 2002;141(5):644–51. [5] Golden NH, Iglesias EA, Jacobson MS, Carey D, Meyer W, Schebendach J, et al. Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab Jun 2005;90(6): 3179–85. [6] Rudge S, Hailwood S, Horne A, Lucas J, Wu F, Cundy T. Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment. Rheumatology (Oxford) Jun 2005;44(6):813–8. [7] El-Husseini AA, El-Agroudy AE, El-Sayed MF, Sobh MA, Ghoneim MA. Treatment of osteopenia and osteoporosis in renal transplant children and adolescents. Pediatr Transplant Aug 2004;8(4):357–61. [8] Brown JJ, Zacharin MR. Safety and efficacy of intravenous zoledronic acid in paediatric osteoporosis. J Pediatr Endocrinol Metab Jan 2009;22(1):55–63. [9] Vuorimies I, Toiviainen-Salo S, Hero M, Makitie O. Zoledronic acid treatment in children with osteogenesis imperfecta. Horm Res Paediatr 2011;75(5):346–53. [10] Panigrahi I, Das RR, Sharda S, Marwaha RK, Khandelwal N. Response to zolendronic acid in children with type III osteogenesis imperfecta. J Bone Miner Metab Jul 2010;28(4):451–5. [11] Sbrocchi AM, Forget S, Laforte D, Azouz EM, Rodd C. Zoledronic acid for the treatment of osteopenia in pediatric Crohn's disease. Pediatr Int Oct 2010;52(5): 754–61. [12] August KJ, Dalton A, Katzenstein HM, George B, Olson TA, Wasilewski-Masker K, et al. The use of zoledronic acid in pediatric cancer patients. Pediatr Blood Cancer Apr 2011;56(4):610–4.
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Bone j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b o n e
Original Full Length Article
Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis Peter J. Simm a,⁎, Jesper Johannesen a, Julie Briody c, Mary McQuade a, Brian Hsu d, Corinne Bridge d, David G. Little b, d, Christopher T. Cowell a, b, Craig F. Munns a, b a
Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia Department of Paediatrics and Child Health, University of Sydney, Sydney, Australia c Department of Nuclear Medicine, The Children's Hospital at Westmead, Sydney, Australia d Department of Orthopaedic Surgery, The Children's Hospital at Westmead, Sydney, Australia b
a r t i c l e
i n f o
Article history: Received 10 March 2011 Revised 16 June 2011 Accepted 19 July 2011 Available online 28 July 2011 Edited by: Robert Recker Keywords: Osteopenia Bone fragility Bisphosphonates Zoledronic acid Fracture
a b s t r a c t There are limited data on the use of bisphosphonate therapy for secondary osteoporoses in childhood, and no previous reports of the use of zoledronic acid in this group. We report 20 children with a variety of underlying primary diagnoses with associated secondary osteoporosis, who were treated with 3 monthly zoledronic acid for 2 years (annualised dose 0.1 mg/kg/year). There was a significant improvement in lumbar spine (by 1.88 SD ± 1.24 over first 12 months, p b 0.001) and total bone mineral density as assessed by dual energy absorptiometry (DXA) scans, with a similar increase in bone mineral content for lean tissue mass (mean increase 1.34 SD in first 12 months, p b 0.001). Bone turnover was reduced with a suppression of both osteocalcin and alkaline phosphatase in the first 12 months of treatment. Skeletal architecture was improved, with increased second metacarpal cortical thickness from 2.44 mm to 2.72 mm (p b 0.001) and improved vertebral morphometry, with 7 patients who had vertebral wedging at baseline showing improved anterior (p = 0.017) and middle (p = 0.001) vertebral height ratios. Aside from well reported transient side effects with the first dose, there were no adverse effects reported. No adverse effects on anthropometric parameters were seen over the course of the study. Despite all patients having sustained fragility fractures prior to treatment, no fractures were reported during the study period. Further evidence is required to confirm efficacy, with long term follow up required to assess the impact of treatment on fracture risk. Crown Copyright © 2011 Published by Elsevier Inc. All rights reserved.
Introduction Childhood and adolescence are critical periods for optimising bone strength, which is itself determined by bone size, geometry, quality, and mass — variables that are influenced by genetic factors, physical activity, nutrition and hormones [1]. For children with genetic skeletal disorders or chronic disease, bone strength is often compromised increasing the lifetime risk of osteoporosis [1]. In children with chronic illnesses the increased risk of fragility fracture are predominantly due to two factors. Firstly, there is the impact of the underlying condition (for example reduced mobility or poor nutrition) on skeletal development and secondly, the negative effect on bone mass accrual of medications (for example glucocorticoids) used to treat the chronic illness [2]. The incidence of vitamin D deficiency is also increased in children with chronic disease, which can have a negative effect on bone development. ⁎ Corresponding author at: The Children's Hospital at Westmead, Institute of Endocrinology and Diabetes, Westmead NSW 2145, Australia. Fax: + 61 2 9845 3170. E-mail address: [email protected] (P.J. Simm).
The clinician is therefore required to identify children at greatest risk for future fragility fracture based on these potential risk factors. Dual energy x-ray absorptiometry (DXA) is a frequently used measure of bone mass and density. Recent data showing an association between low bone density as assessed by DXA and fractures in children [3], would support its use to monitor for children at risk of fragility fracture and follow treatment aimed at reducing fracture risk. Radiographs for vertebral morphometry and second metacarpal cortical thickness can also be used to assess bone development in children [1]. When used in conjunction with DXA, these radiological evaluations can give a greater understanding of the state of bone health and effect of treatment. Bisphosphonates are being administered with increasing frequency to children with secondary osteoporosis, however, the efficacy and safety of these agents require further clarification. A Cochrane review found only four randomised controlled trials (RCT) of significant use of bisphosphonates in children and adolescents with secondary osteoporosis [4–7]. The numbers in each study were small (6–20 patients in the treatment arm) and follow-up short (12 months in
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each study). While all of these trials showed within-group benefit in improved bone mineral density, only one clearly showed a betweengroup benefit [7]. None of these studies used zoledronic acid. To date a small number of studies have been published using longer term zoledronic acid in paediatric patients with primary osteoporoses such as osteogenesis imperfecta [8–10]. A single dose of Zoledronic acid has also been shown to improve bone density in children with Crohn's disease [11]. Zoledronic acid has also been trialled for management of skeletal metastases in paediatric cancer patients, with no reports of significant adverse events [12]. A review of interventions for bone health in cerebral palsy found only 3 studies using bisphosphonates, none of which was using zoledronic acid [13]. No study has looked at the long term effects of zoledronic acid in secondary osteoporoses and there have been no studies powered to assess fracture rate reduction. Despite the growing use of bisphosphonates in children and adolescents for an increasing variety of conditions, long term studies are still required to fully address issues of safety and efficacy [14]. This case-series reports 20 children with secondary osteoporosis, defined as total body BMD (TBMD) and/or lumbar spine BMD (LSBMD) z-score b −2.0 and at least one pathological low trauma fracture or bone pain, treated with zoledronic acid for an average of 1.24 years and followed for 2 years after initiation of treatment. Material and methods Subjects 20 children (9 males and 11 females) with a mean age of 9.6 ± 4.7 years (range: 3.3–16.5 years), were diagnosed with secondary osteoporosis defined as TBMD and/or LSBMDb −2.0 and at least one pathological low trauma fracture or bone related pain [15]. Their underlying diagnoses were: immobility secondary to cerebral palsy (10 patients), 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 osteopenia/osteoporosis of unknown origin [2]. Following approval by the Hospital Drug Committee zoledronic acid was administered as part of our routine care. Permission to undertake and report this retrospective chart review was obtained from the Institutional Ethics Committee. Treatment protocol Intravenous zoledronic acid was given at an initial dose of 0.0125 mg/kg with the second dose given 12 weeks later at 0.025 mg/kg. All subsequent doses were 0.025 mg/kg given at 12 weekly intervals. The calculated dose of zoledronic acid was diluted in 50 ml 0.9% NaCl and infused over 30 min. The annualised dose was 0.10 ± 0.02 mg/kg given over a period of 1.7 ± 0.7 years (range: 0.5– 2 years). Prior to the start of treatment, all children were assessed by a paediatric endocrinologist and all had serum 25-hydroxyvitamin D, urea and creatinine concentrations within quoted reference ranges and normal renal ultrasound scans. Children were commenced on a multivitamin containing 400 IU vitamin D per day and prescribed calcium supplementation if their dietary intake was less than the recommended daily intake [1]. Anthropometry, blood analysis and DXA scans Height, weight and calculated body mass index (BMI) standard deviation score (SD) as well as mineral homeostasis were evaluated at baseline, 1 and 2 years: calcium (Ca), phosphorus (Pi), parathyroid hormone (PTH), alkaline phosphate (ALP), osteocalcin (OST) and 25-hydroxyvitamin D (25-OHD). A SAS programme that applies the 2000 CDC growth chart data was used to calculate anthropometric SD
[16]. (http://www.cdc.gov/growthcharts/computer_programs.htm). Ca, Pi 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, California, USA). 25-OHD was measured by radioimmunoassay (Diasorin, Stillwater, Minn, USA). OST was determined using solid phase chemiluminescent immunoassays (Immulite 1000, Siemens, Los Angeles, USA). Bone mineral density (BMD) at baseline, 1 and 2 years was determined by DXA using a Lunar Prodigy (GE Lunar Radiation Corp, Madison, Wisconsin, USA). Subjects were positioned, scanned and analysed according to standard manufacturer recommendations. Measurements were analysed using software version 8.10. Total body, postero-anterior lumbar spine and proximal femur scans were performed on all subjects. These provided total bone mineral density, adjusted for age (TBMD), lumbar spine bone mineral density (LSBMD), total bone mineral content (TBMC), and total bone mineral content adjusted for lean tissue mass ratio (BMCLTM).The volumetric LSBMD was calculated as per Carter et al. [17], in order to reduce the influence of height on the LSBMD. The DXA value conversion to age, height and sex-matched SD-scores (Z-scores) were based on previously published CHW normative data [18,19] using an expanded dataset (n= 650) and updated software version 4.7. The BMCLTM was calculated on the basis of previously published CHW normative data [20]. These ancillary variables help explain the aetiology of the BMC and BMD measurements, especially in the paediatric population when both bone and body size change dramatically during growth. Postero-anterior radiographs of the left hand at baseline and 1 year were evaluated by paediatric radiologists to calculate bone age as per Greulich et al. [21]. Metacarpal cortical thickness was measured on the bone age X-ray at the midpoint of the 2nd metacarpal (using Magicweb software, Visage Imaging, Inc, Andover MA). Metacarpal cortical area was calculated by estimating the total area using the total diameter of the bone, and subtracting the medullary area, calculated by measuring the internal diameter. Lateral thoraco-lumbar spine radiographs were taken at baseline, 1 and 2 years. These were assessed for spondylolisthesis and vertebral morphology. Morphology was determined by measuring the posterior, mid-body and anterior vertebral body height, and expressing these as a ratio of the inferior length of the vertebral body as described previously [22]. Significant vertebral wedging was defined as a greater than 15% decrease in anterior vertebral body height as compared to the posterior height [23]. Statistical analysis Means and standard deviations are reported for all data. Data was assessed for normality. Student t-test was used comparing groups at entry. Repeated measurement was used analysing data over the 2 years follow-up. For data that was not normally distributed Wilcoxon's non-parametric paired test was employed. A p-value of b0.05 was selected as the level of significance for this study before the data analysis. Results Baseline anthropometry characteristics for height, weight and BMI are shown in Table 1. No difference between genders was observed. Baseline TBMD, LSBMD, TBMC and BMCLTM measured by DXA are also found in Table 1, with again no gender difference observed. Height, weight, BMI and bone age No significant difference was seen in height, with the mean Z score at baseline − 1.58, compared with −2.06 at 24 months, (p = 0.17).
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5
Table 1 Baseline demographics according to gender.
***
4
Gender
All
Male
Female
N
20
9
11
Age (year) Height SD Weight SD BMI SD TBMD (z-score) Areal LSBMD (z-score) TBMC (z-score) BMC_LTM (z-score)
9.6 ± 4.7 − 1.6 ± 2.0 − 1.8 ± 1.8 − 12 ± 2.8 − 1.5 ± 1.6 − 2.7 ± 1.4 − 1.9 ± 1.3 − 0.7 ± 3.4
10.2 ± 4.4 − 1.4 ± 1.4 − 1.6 ± 1.8 − 0.9 ± 2.2 − 1.5 ± 1.5 − 2.1 ± 1.5 − 1.5 ± 0.8 − 1.0 ± 3.6
9.1 ± 5.1 − 1.7 ± 2.4 − 2.0 ± 1.9 − 1.3 ± 3.2 − 1.5 ± 1.8 − 3.3 ± 1.2 − 2.3 ± 1.6 − 0.5 ± 3.3
3
p-Value, gender
*
2 1 Z score 0 (SD) -1
0.61 0.41 0.82 0.75 0.99 0.07 0.26 0.79
-2 -3 -4 -5
***
*
(a)
(b)
(c)
(d)
0 months 12 months 24 months
Legend: mean ± SD.
Similarly, no significant change was seen in weight or BMI SD from baseline to 2 years (data not shown). Bone age increased in accordance with chronological age from pre treatment (9.3 ± 5.0) and at 2 years 11.0 ± 5.0 (p = 0.91). Background fracture history The mean number of fractures sustained prior to commencing the study was 1.7 (range 1–6). 6 patients had sustained vertebral fracture(s) alone, 12 had sustained long bone fracture(s) and 2 had sustained both long bone and vertebral fracture(s). No fractures were recorded in the 20 subjects during the study period. Biochemistry There were significant reductions seen from baseline to 1 year post treatment in the bone turnover markers alkaline phosphatase and osteocalcin, while other biochemical parameters remained stable (Table 2). DXA scanning A significant increase was demonstrated in total BMD Z scores (mean − 1.51 ± 1.59 at baseline to − 1.04 ± 1.51 at 24 months, p = 0.04) and lumbar spine BMD Z scores (− 2.72 ± 1.4 at baseline to −0.46 ±1.47 at 24 months, p b 0.001). Similarly, there was a marked increase in the BMCLTM Z-score (−0.72± 3.27 at baseline to 1.39± 2.64 at 24 months, p b 0.001) (Figs. 1a–c). The volumetric age adjusted LSBMD Z-score also increased over the 2 year period (mean −1.84, ±1.01 at baseline to 0.42, ±1.97 at 24 months, p = 0.02) (Fig. 1d). The greatest increase in LSBMD Z-score occurred during the first year of treatment with an increase of 1.88 ± 1.24 and 0.38 ± 0.70 (p b 0.001) over the 1st and 2nd year periods respectively. A similar trend was seen for volumetric LSBMD Z-score, with an increase of 1.57 ± 1.07 and 0.69 ± 1.47 (p = 0.08) over the 1st and 2nd year periods respectively. Metacarpal/vertebral morphometry from plain X-rays Metacarpal parameters were available in 12 patients, with pretreatment films compared with post-treatment (median 27 months
Fig. 1. DXA scan results for patients with secondary osteoporosis treated with zoledronic acid showing improvement in all measures over the course of the study. (a) total body areal bone mineral density Z scores, (b) lumbar spine areal bone mineral density Z scores, (c) bone mineral content for lean tissue mass Z scores, and (d) lumbar spine volumetric bone mineral density Z scores. * represents p b 0.05, *** represents p b 0.001 (baseline compared with 24 month results).
post commencement of ZA). Mean cortical thickness increased from 2.44 mm to 2.72 mm (p b 0.001), while mean cortical area increased from 60.19 mm 2 to 70.18 mm 2 (p b 0.001) (Fig. 2). Spine X-rays were available pre treatment for 12 patients, with 7 showing evidence of anterior vertebral wedging or crush fractures prior to the commencement of bisphosphonate treatment. Vertebral morphometry on affected vertebrae in these 7 patients showed a significant improvement in both anterior and middle vertebral height ratios after 2 years of treatment, leading to improved vertebral shape (Fig. 3). Adverse effects of treatment Aside from transient first dose side effects which have been described previously in the Children's Hospital at Westmead cohort [24] no adverse effects were noted, with ongoing dental review revealing no cases of osteonecrosis of the jaw. There were no fractures or spondylolistheses during the treatment or follow-up periods. All patients had serum calcium levels checked 48–72 h after their first infusion, with no significant hypocalcaemia seen. Each patient was treated with supplemental calcium and calcitriol for 3–7 days following the first infusion and Vitamin D sufficiency was maintained throughout the study. Discussion This is the first report of 24 month follow-up zoledronic acid therapy data in children with secondary osteoporosis. Short-term zoledronic acid therapy was safe and associated with increased BMD (especially in the lumbar spine) and cortical thickness. This change was consistent with a real increase in bone mass accrual, as there was no significant change in height Z score and bone age progressed at the expected rate, meaning that accelerated maturation was not driving the observed increase in BMD. Importantly, there was also evidence of
Table 2 Biochemical values over 2 years of zoledronic acid treatment (values reported as mean ± SD) NS: not significant — p N 0.05.
Calcium (mmol/L) Phosphate (mmol/L) Alkaline phosphatase (U/L) Parathyroid hormone (pmol/L) Osteocalcin (nmol/L)
Baseline
1 year
2 years
p Value (1st year vs baseline)
2.34 ± 0.11 1.35 ± 0.23 236.9 ± 179.29 4.3 ± 2.66 7.5 ± 5.04
2.39 ± 0.11 1.41 ± 0.29 185.5 ± 134.65 4.0 ± 2.58 3.9 ± 2.33
2.36 ± 0.14 1.39 ± 0.17 205.13 ± 177.29 4.5 ± 3.35 4.7 ± 3.42
NS NS 0.006 NS 0.026
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Periosteal diameter Endocortical diameter
Fig. 2. Representative patient pre-treatment X-ray of second metacarpal (left) and post treatment X-ray (right) demonstrating increased cortical thickness. Across all subjects, mean cortical thickness increased from 2.44 mm to 2.72 mm (p b 0.001).
vertebral modelling. These data would be in keeping with an increase in bone strength. Growth was not affected by zoledronic acid and as expected, bone turnover was reduced as evidence by the reduction in ALP and osteocalcin. The greatest increase was seen in the first 12 months after commencing therapy, with the majority of children demonstrating normalisation of lumbar spine z-scores (areal and volumetric) after 2 years of treatment. Further data are required to determine the optimal treatment thereafter, but bisphosphonate therapy may then be able to be ceased or continued at a reduced dose. The improved spinal shape is also consistent with previous reports in osteogenesis imperfecta [22] and chronic recurrent multifocal osteomyelitis [25], which further supports the importance of bisphosphonate treatment in young people with vertebral wedging or crushing. Bisphosphonate treatment outcome data from adult studies, and those in children with osteogenesis imperfecta, are important guides in developing the optimal treatment regimen for children with secondary osteoporosis. The best treatment regimen, in terms of choice of drug, route of administration, dosing schedule and treatment duration, remains to be determined and large controlled trails are required. While 3 monthly treatment gave good response in
Fig. 3. Vertebral morphometry — figure depicts a representation of the average ratios of posterior height, mid height and anterior height of vertebral bodies showing anterior wedging or crush fractures in 7 patients. Pre treatment ratios are compared with those seen after 2 years of treatment. There has been a significant increase in mid height ratio (p = 0.017, represented by *) and anterior height ratio (p = 0.001, represented by **).
this study, it may be possible to get similar results if the zoledronic acid was administered less frequently, for example 6 monthly. It is unlikely that extending beyond 6 months would be possible due to the requirement to dose new bone formed with growth and the aim to influence bone modelling as well as remodelling in children. This is evident by the improvement in vertebral shape that is possible in children compared to adults. In children with secondary osteoporosis the importance of other management aspects of bone health should not be forgotten. These include maximising physical activity, ensuring timely pubertal progression, providing adequate intake of calcium and vitamin D and minimising exposure to osteotoxic medication [1]. Ensuring a safe home and school environment so as to limit the risk of accidental trauma is also of great importance. When combined with an effective bisphosphonate regime, best outcomes are likely. Despite evidence of efficacy in a number of clinical contexts in paediatrics, there are still some concerns about the safety of bisphosphonate therapy in children [26,27]. There are a number of recognised side-effects including first dose effects of hypocalcaemia and an acute ‘flu-like’ reaction (as discussed above) [24], with disturbed metaphyseal modelling [28], reduced bone turnover [29] and persistence of calcified cartilage in the metaphysis [30]. Given the long half life in the skeleton, there is also a potential effect on the developing foetus if the mother has been previously treated with these agents [31]. Bisphosphonate-related osteonecrosis of the jaw is well described in adult patients however, there are no reported cases in paediatric patients [32]. Due to these concerns, and the need for paediatric patients to be carefully monitored for such side effects, the use of bisphosphonates in paediatrics should be restricted to centres with experience in the use of this therapy in childhood. In conclusion, our study highlights that zoledronic acid is an effective agent in young people with secondary osteoporosis, with a wide range of primary diagnoses, in causing an improvement in bone density. Zoledronic acid also improved bony architecture with increased metacarpal thickness and reconstitution of vertebral shape seen in these patients. The treatment was well tolerated with no significant side effects. Longer term studies with a larger patient group are required to address the issue of whether improving bone density leads to a long term reduction in fracture risk, but the absence of fractures in a 2 year period in this group, all of whom had previous fragility fractures, is reassuring. Treatment that can reduce morbidity in this patient group that already experience significant burden from their underlying disorders should be strongly considered when appropriate.
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