International Journal of Rheumatic Diseases 2015; 18: 287–293
SYSTEMATIC REVIEW
Treatment of glucocorticoid-induced low bone mineral density in children: a systematic review Arundathi JAYASENA,1 Navoda ATAPATTU1 and Sarath LEKAMWASAM2 1 Paediatric Endocrinology, Lady Ridgeway Hospital for Children, Colombo, and 2Department of Medicine, Faculty of Medicine, Centre for Metabolic Bone Diseases, Galle, Sri Lanka
Abstract Aims: The aim of this systematic review was to evaluate, critically, the treatment options used in the management of bone loss associated with glucocorticoid (GC) use among children. Methods: We performed a systematic search using PubMed, Cochrane clinical trial registry, Clinicaltiral.gov and Ovid databases (1 March, 2013). The search resulted in 34 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by two authors. Results: Four studies have compared the effectiveness of bisphosphonates in the treatment of GC-induced low bone mineral density (BMD) in children. Remaining studies were on menatretenone + alfacacidol versus alfacalcidol alone, calcium + vitamin D versus placebo and alfacalcidol versus menatetrenone. In the four studies, bisphosphonates have shown the ability either to improve BMD or prevent bone loss associated with GC use in children. However, alendronate either in oral or intravenous routes and oral pamidronate were the only bisphosphnates that have been studied in children. Vitamin K2 (menatetrenone) combined with alfacalcidol has also preserved BMD in children on long-term GC therapy. Calcium combined with alfacalcidol has also prevented bone loss, greater than menatetrenone. Calcitriol together with Calcium in conventional doses has retarded bone loss, although the combination could not completely prevent the process. Conclusions: Vitamin D derivatives such as calcitriol or alfacalcidol together with adequate calcium can be considered suitable treatment options to be started simultaneously when long-term GC therapy is needed in children. For children who have been on GCs or have already lost BMD, either oral pamidronate or alendronate in oral/intravenous routes can be considered based on the availability. Key words: children, bone mineral density, glucocorticiods.
INTRODUCTION Glucocorticoids (GCs) are widely used in pediatric practice. Long-term systemic GC therapy is associated with many side-effects, including low bone mineral density (BMD) and fragility fractures.1–3 Most studies examining the underlying mechanisms and pathophysiology
Correspondence: Professor Sarath Lekamwasam, MD, FRCP, PhD, Department of Medicine, Faculty of Medicine, Centre for Metabolic Bone Diseases, Galle, Sri Lanka. Email: [email protected]
of GC-induced bone loss have used adult subjects and studies among children are limited. The bone loss associated with GC use is rapid, initially, and continues as long as the drug is continued.2 The association between GC use and fractures among adults is well known. Van Staa et al. found baseline BMD to predict incident vertebral fractures among premenopausal women taking GCs. While each 1 unit decrease in T-score was associated with 1.85 relative risk of vertebral fracture (95% CI = 1.06–3.21), 10 mg increase of daily prednisolone dose was associated with a relative risk of 1.62 (95% CI = 1.11–2.36).4
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Y. A. Arundathi Jayasena et al.
In recent years, the issue of low bone density in children and adolescents has attracted much attention. GC-induced osteoporosis (GIO) in children is a very complex entity and it is further complicated by the limitations in available data. Furthermore, the current lively debate on the definition of osteoporosis in children, including GIO, illustrates the need for further research in this field. The diagnosis of osteoporosis during childhood and adolescence is based on the comparison of BMD with healthy subjects of the same age and sex, but the situation is compounded by the extensive inter-individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). Although BMD Z-score values below 2 and 1 are generally considered as osteoporosis and osteopenia, respectively, the diagnosis of osteoporosis in children and adolescents is only made in the presence of low BMD and at least one fragility fracture, by most specialists in the field. Due to the uncertainty of the definition, we prefer to use the term GC-induced low BMD (GC-LBMD) rather than osteoporosis or osteopenia when we address children in this review. However, for adults the term GIO is used in this review. Treatment of GC-LBMD in children is understudied and clinical trials involving children on GCs are sparse. Treatment options in GC-LBMD in children are greatly limited and management guidelines are not well established. The guidelines developed by the Royal Collage of Physicians, London in 2002 included only a brief account on children and the information given was not based on clinical trials.5 Similarly, American Rheumatology Council guidelines published in 2010 and Canadian guidelines published in 2002 do not address the issue of GC-LBMD management among children.6,7 The most recent framework provided to develop guidelines on GIO by the International Osteoporosis Foundation also did not consider subjects below 18 years of age.8 This leaves many children on GCs either untreated or partially treated. The situation is more critical in countries where screening facilities for low bone mass is restricted and general awareness of providing bone protection for patients on GCs is low. We conducted a systematic review on treatment of GC-LBMD in children based on the published literature acquired after a systematic search. The aim of the search was to critically evaluate the treatment options used in the treatment of GC-LBMD among children.
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METHOD The first search was conducted in the free-text version of PubMed using search terms ‘glucocorticoid* OR corticosteroid* OR steroid*’ AND ‘osteoporosis OR bone density OR fracture* OR height velocity’. The search was limited to the clinical trials and age below 18 years. The search was extended to the MeSH database using ‘glucocorticoids’ [Pharmacological Action] AND ‘Osteoporosis/chemically induced’ [Mesh] AND (Clinical Trial [ptyp] AND English [lang] AND (‘infant’ [MeSH Terms] OR ‘child’ [MeSH Terms] OR ‘adolescent’ [MeSH Terms])). We also used the ‘Clinical queries’ option of PubMed to trace relevant clinical trials. Apart from PubMed, Cochrane clinical trial registry, Clinicaltiral.gov and ovid databases were also searched using the appropriate search terms to retrieve the relevant literature. The search methodology we used is very similar to that used by the International Osteoporosis Foundation – European Calcified Tissue Society (IOF-ECTS) guidelines working group in 2012, when formulating a framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis.8 Two authors (AJ and SL) selected literature, blinded to each other, based on the following inclusion and exclusion criteria. Inclusion criteria were: systemic GCs, children below 18 years, clinical trials and outcome measures of bone mineral density, incidence of fractures or height velocity. Exclusion criteria were: patients on inhaled or topical steroids, methods other than clinical trials, outcome measure of biochemical markers and post-transplant recipients. Articles were categorized as ‘included’, ‘excluded’ and ‘doubtful’ by the two authors and the agreement between them was assessed. They decided on ‘doubtful’ articles by consensus. This process selected seven clinical trials on treatment of GC-induced low BMD in children. Data extracted were: age, underlying diseases, dose and duration of GC therapy, type of active treatment, care given to the control group, duration of study, change of outcome variables before and after treatment and the level of statistical significance.
RESULTS The PubMed search resulted in 36 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by the two
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authors.9–15 The kappa value for the agreement between two authors was 0.8. Searches in other databases did not yield any additional literature. The information related to baseline characteristics of subjects and type of care offered to the trial participants are summarized in Table 1. Changes in the outcome measures before and after treatment are shown in Table 2. All studies were clinical trials on patients of pediatric and adolescent age groups. The underlying diseases requiring GCs varied from autoimmune disorders to nephritic syndrome and nephropathy (Table 1). The duration of GC therapy also varied between the studies. In two of the studies drugs to prevent bone loss were started simultaneously with corticosteroid therapy,11,13 whereas in the remaining five clinical trials the efficacy of treatment was assessed in children who had received GCs for more than 3 months. Four studies9–11,14 compared the effectiveness of bisphosphonates in the treatment of GC-LBMD in children. Of these, two studies compared effectiveness of either intravenous (i.v.) or oral pamidronate over placebo.10,11 The other two studies assessed efficacy of intravenous alendronate9 or once weekly oral alendronate14 over placebo. The remaining studies were on menatetrenone + alfacacidol versus alfacalcidol alone,12 calcium + vitamin D versus placebo13 and alfacalcidol versus menatetrenone.15 The duration of clinical trials varied from 3 months to 2 years and sample size from 11 to 44 (Table 1). All included clinical trials used either change in absolute BMD Z-score or percentage BMD change as outcome variables (Table 2). Only two of the studies14,15 assessed height (Ht) velocity. None of the studies assessed the incidence of fractures during the follow-up period.
Effects of bisphosphonates Alendronate in i.v. and oral forms and oral pamidronate were effective in reducing bone loss associated with systemic GC therapy in children. In the study by Kim et al.11, oral pamidronate prevented BMD loss among treated subjects (mean BMD 0.644 and 0.647 before and after treatment) while the control group on calcium alone showed a significant decline in BMD (BMD 0.654 and 0.631 before and after treatment, P = 0.017). Although BMD changes were not explicitly shown, Inoue et al.9 observed similar results with intravenous alendronate. According to Rudge et al.14 once-weekly alendronate significantly increased the volumetric bone density of the lumbar spine (P = 0.013). The attempted randomized controlled trial with i.v.
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pamidronate by Brown and Zacharin10 did not show any significant treatment effect as a consequence of trial failure.
Other therapies Inoue et al. observed a 4.1% increase in BMD with i.v. menatretenone combined with alfacalcidol. Alfacalcidol alone given to the control group resulted in 1.3% decline in BMD.9 Authors concluded that i.v. menatretenone together with alfacalcidol is an effective treatment to prevent bone loss in children on GCs. However, Rianthavorn et al. showed that calcium supplementation along with alfacalcidol can prevent further bone loss to a greater extent than menatetrenone as the BMD Z-score ( 1.1 0.8 to 1.5 0.7 and 1.2 1.0 to 1.6 1.2 in menatetrenone and in alfacalcidol groups, respectively) at 12-month followup was significantly decreased from baseline in the menatetrenone group.15 Bak et al.13 found calcium and calcitriol retarded BMD loss among children receiving GCs (4.6% and 13.1% reduction in BMD with calcitriol + calcium and placebo, respectively). It is noteworthy that in the above trial, calcitriol and calcium were started simultaneously with GC therapy and it can be considered a prevention trial. However, the trial lasted only 8 weeks and lacks long-term follow-up BMD results.
DISCUSSION In this systematic review our aim was to analyze the available literature on treatment of GC-LBMD in children. We found only a very limited literature base and it did not allow us to assess the consistency of the results between studies. Furthermore, the trials included in this review have a restricted validity. When these trials were evaluated using the Jadad scoring system which is a standard scoring system to evaluate randomized controlled trials,16 the majority of them failed to gain a higher validity score. The Jadad score awards points for the acceptability of randomization as well as blinding and accounting for drop-outs. Many studies included in this analysis did not mention the method of randomization, blinding process or drop-outs. The attempted randomized controlled trial with i.v. pamidronate versus calcium and calcitriol by Brown and Zacharin10 illustrates the practical difficulties in conducting a randomized controlled trial in children due to unpredictable pattern of remissions and relapses, difficulty in getting consent and thus unacceptable drop-out rate. None of the studies have assessed the incidence of
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Rudge et al. (2005) Rianthavorn et al. (2012)
Inoue et al. (2001)
Kim and Cho (2006)
Inoue et al. (2008) Brown and Zacharin (2005) Bak et al. (2006)
Author/year
10
11
10
10
8
20
20
11
22
7
5
22
6
Control group
5
Study group
Sample size
Not specified
Chronic illnesses
Autoimmune diseases
Steroid-sensitive nephrotic syndrome Nephropathy
Autoimmune diseases Not specified
Underlying disease requiring glucocorticoid therapy
Alfacalcidol group 0.27 0.14 Menatetrenone group 0.31 0.17
0.1–2.4 mg/kg/day
Subjects 0.22 0.05
Intravenous pulse methylprednisolone+ oral prednisolone 1 mg/kg/day Controls 0.18 0.1
2
Minimum 18 months
Controls 33 15 months Subjects 37 13 months 0.3–7 years
Once weekly oral Alendronate Alfacalcidol + Calcium
Alfacalcidol + menatetrenone (vitamin K2)
Oral pamidronate + calcium
3 months (5 cycles)
1 year
1 year
12 weeks
3 months
8 weeks
Calcium + calcitriol
8 weeks
2 years
Duration of treatment
2 years
> 3 months
> 0.2
Type of treatment for glucocorticoid-induced low bone mineral density Intravenous alendronate + calcium + vitamin D Intravenous pamidronate
6 months
Duration
Not mentioned
Dose mg/kg/day
Glucocorticoid therapy
Table 1 Baseline characteristics and type of care received by trial participants
Menatetrenone + calcium
Oral placebo
Alfacalcidol
Oral calcium
Ca CO3 + vitamin D No treatment
No treatment
Care for control/ other group
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International Journal of Rheumatic Diseases 2015; 18: 287–293
0.0029
< 0.001
1.3 2.4
3.0 4.0%
4.1 3.2
8.7 5.2%
< 0.01
0.0029 0.156
0.017
< 0.001
Rianthavorn et al. (2012)
Kim and Cho (2006) Inoue et al. (2001) Rudge et al. (2005)
BMD, bone mineral density
< 0.05
0.013
0.20 0.22 (Z-score) 0.52 0.18 to 0.45 0.16 g/cm2 0.654 0.069 to 0.631 0.070 g/cm2 0.704 0.147 g/cm2 0.255 0.013 to 0.276 0.011 g/cm3 Menatetrenone group 0.64 0.07 g/cm2 0.001
> 0.5
Not mentioned
0.03
0.04 0.48 0.57 (Z-score) 0.54 0.15 to 0.51 0.10 g/cm2 0.644 0.189 g/cm2 to 0.647 0.214 g/cm2 0.643 0.149 g/cm2 0.266 0.011 g/cm3 to 0.307 0.008 g/cm3 Alfacalcidol group 0.71 0.15 g/cm2
BMD
Not mentioned
Inoue et al. (2008) Brown and Zacharin (2005) Bak et al. (2006)
P-value Year
Subjects
P value
BMD
Controls Change in BMD Author/
Table 2 Changes in the outcome measures of the seven selected clinical trials
4.6 2.1%
6.6 4.0%
> 0.05
P-value between groups Controls BMD P between groups
Subjects BMD
Percentage change in BMD
Glucocorticoid-induced low BMD in children
International Journal of Rheumatic Diseases 2015; 18: 287–293
fractures which is an important clinical measure of bone metabolism in children. Only two of the studies14,15 have assessed Ht velocity. Limited information from this review reveals that bisphosphonates are effective in the treatment of GCLBMD in children. However, alendronate and pamidronate are the only bisphosphnates that have been studied in children so far. Pamidronate in oral form is shown to be effective but the effectiveness of the i.v. form which is widely used in clinical practice remains unknown. Vitamin K2 (menatetrenone) with alfacalcidol has also preserved BMD in children on long-term GC therapy. However, calcium supplementation along with alfacalcidol can prevent further bone loss to a greater extent than menatetrenone. Calcitriol together with calcium in conventional doses appears to retard bone loss although the combination does not completely prevent the process. The possible retardation of bone loss with vitamin D derivatives was evident in the Inoue et al.9 study as well. In this study, the control group who were given alfacalcidol lost BMD only by 1.3%. Meta-analyses have consistently shown that bisphosphonates are effective in the prevention and treatment of GIO among adults.6,17,18 Several studies have reported the efficacy of vitamin K2/menatetrenone in the treatment of GIO, adult form, in Japan.19,20 Vitamin K2/menatetrenone along with vitamin D3 appear to have a protective effect on lumbar BMD in GIO.21,22 Furthermore, vitamin K2 is shown to have a preventive effect on occurrence of new fractures in osteoporosis.23– 25 Thus the findings of Inoue et al. are comparable with the existing data in the adult population, although latest evidence from Rianthavorn et al.15 show that alfacalcidol can prevent further bone loss to a greater extent than menatetrenone. Nevertheless menatetrenone lacks approval for the treatment of osteoporosis in any part of the world and also is not included in any management guidelines related to osteoporosis. However, only two bisphosphonates, namely alendronate and pamidronate have been studied in children up to now. The other bisphosphontes approved to treat adult GIO such as oral risedronate and i.v. zoledronic acid and newer therapeutic modalities such as teriparatide have not been studied in children so far. However, the possible carcinogenicity of teriparatide exposure, especially in children, needs to be seriously considered.26 Bone mineral loss associated with GC therapy appears to be a result of direct suppression of osteoblastic bone-forming activity and increased bone resorption
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caused by parathyroid hormone stimulation of osteoclastic activity.26 Bone loss is more pronounced in regions with high content of trabecular bone such as vertebrae, ribs and ends of long bones. In younger individuals, the high rate of bone turnover predisposes to more rapid bone loss.27 Recent data indicates that a rapid loss of bone occurs immediately after the initiation of GC therapy with 10–20% or more loss of trabecular mass occurring over the first 3–6 months.2 Furthermore, diverse effects of GC therapy on body weight, growth velocity and sexual maturation in children may contribute to the acquisition of peak bone mass and future fracture risk. The extent of recovery of growth velocity and bone mass in children after the termination of GC therapy is unknown.2 Although alendronate and pamidronate have been shown to be effective in the treatment of GC-LBMD in children, follow-up studies regarding efficacy, safety and side-effects need to be done. Bisphosphonates in general have many adverse effects and safety concerns. Apart from the well-known upper gastrointestinal sideeffects, the long-term retention of the drug in the body may create problems for young women in the reproductive age when planning pregnancy. Current data is not sufficient to determine whether long-term bisphosphonate therapy has any adverse outcome on the skeletal growth of adolescent children. The long-term growth velocity and fracture risk are more clinically relevant outcome measures and the effect of such therapies on these outcome measures need to be assessed in children on long-term GC therapy. Furthermore, the necessity of proper randomized controlled trials with high validity on newer bisphophonates and other therapeutic modalities such as teriparatide is evident. Until such data are available, clinicians involved in the management of children on long-term GC therapy have limited therapeutic options. Vitamin D derivatives such as calcitriol or alfacalcidol can be considered suitable treatment options to be started simultaneously when long-term GC therapy is needed. For children who have been on GCs, either oral pamidronate or alendronate in oral and i.v. form can be considered based on availability. Although vitamin K especially in combination with vitamin D has prevented bone loss, such therapy cannot be recommended as it lacks Food and Drug Administration approval for the treatment of GIO in adults. Apart from co-prescribing drugs to prevent GCinduced bone loss, clinicians should attempt reducing the dose of GC or completely withdraw them whenever possible. Other measures such as alternate day
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treatment and use of other routes to administer GCs should be considered. The long-term adverse effects of the prophylactic medications discussed above also need to be addressed. While the long-term safety of many drugs has not been adequately assessed, hypercalcemia and hypercalciuria are well-known unwanted effects of vitamin D derivatives.
REFERENCES 1 Van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: A metaanalysis. (Review). Osteoporosis Int 13, 777–87. 2 Buckly LM (2000) Clinical and diagnostic features of glucocorticoid induced osteoporosis. Clin Exp Rheumatol 18, s41–3. 3 Payer J, Brazdilova K, Jackuliak P (2010) Management of glucocorticoid induced osteoporosis: prevalence and emerging treatment options. Drug Healthc Patient Saf 2, 49–59. 4 Van Staa TP, Laan RF, Barton IP, Cohen S, Reid DM, Cooper C (2003) Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 48, 3224–9. 5 Royal College of Physicians, National Osteoporosis Society, Bone and Tooth Society of Great Britain (2002). Glucocorticoid-Induced Osteoporosis—Guidelines for Prevention and Treatment. Royal College of Physicians, London. 6 Grossman JM, Gordon R, Ranganath VK et al. (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid induced osteoporosis. Arthritis Care Res 62, 1515–26. 7 Brown JP, Josse RG (2002) Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. Can Med Assoc J 167 (10 Suppl.), S1–34. 8 Lekamwasam S, Adachi JD, Agnusdei D et al. (2012) Joint IOF-ECTS GIO Guidelines Working Group. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 23, 2257–76. 9 Inoue Y, Shimojo N, Suzuki S et al. (2008) Efficacy of intravenous alendronate for the treatment of glucocorticoid-induced osteoporosis in children with autoimmune disease. Clin Rheumatol 27, 909–12. 10 Brown JJ, Zacharin MR (2005) Attempted randomized controlled trial of pamidronate versus calcium and calcitriol supplements for management of steroid-induced osteoporosis in children and adolescents. J Paediatr Child Health 41, 580–2. 11 Kim SD, Cho BS (2006) Pamidronate therapy for preventing steroid-induced osteoporosis in children with nephropathy. Nephron Clin Pract 102, c81–7. 12 Inoue T, Sugiyama T, Matsubara T, Kawai S, Furukawa S (2001) Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in
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13
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children treated with glucocorticoid and alfacalcidol. Endocr J 48, 11–8. Bak M, Serdaroglu E, Guclu R (2006) Prophylactic calcium and vitamin D treatments in steroid-treated children with nephrotic syndrome. Pediatr Nephrol 21, 350–4. Rudge S, Hailwood S, Horne A, Lucas J, Wu F, Cundy T (2005) Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment. Rheumatology 44, 813–8. Rianthavorn P, Pisutikul K, Deekajorndech T, Tepmongkol S, Suphapeetiporn K (2012) Prevention of bone loss in children receiving long-term glucocorticoids with calcium and alfacalcidol or menatetrenone. J Pediatr Endocrinol Metab 25, 307–12. Moher D, Jadad AR, Tugwell P (1996) Assessing the quality of randomized controlled trials: current issues and future directions. Int J Technol Assess Health Care 12, 195– 208. Homik J, Cranney A, Shea B et al. (2000) Bisphosphonates for steroid-induced osteoporosis. Cochrane Database Syst Rev 2: CD001347 (Review). Kanis JA, Johansson H, Oden A et al. (2004) A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 19, 893–9. Iwamoto J, Takeda T, Ichimura S (2003) Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J 44, 508–16.
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20 Tanaka I, Ohshima K (2003) A longitudinal study of diagnosis and treatment for corticosteroid-induced osteoporosis. Osteoporosis Japan 11, 11–4. 21 Yonemura K, Fukasawa H, Fujigaki Y, Hishida A (2004) Protective effect of vitamins K2 and D3 on prednisoloneinduced loss of bone mineral density in the lumbar spine. Am J Kidney Dis 43, 53–60. 22 Yonemura K, Kimura M, Miyaji T, Hishida A (2000) Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral in patients with chronic glomerulonephritis. Calcif Tissue Int 66, 123–8. 23 Iinuma N (2005) Vitamin K2 (menatetrenone) and bone quality. Clin Calcium 15, 1034–9. 24 Shiraki M, Shiraki Y, Aoki C, Miura M (2000) Vitamin K2 (Menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res 15, 515–21. 25 Iwamoto J, Takeda T, Ichimura S (2003) Treatment with vitamin D3 and/or vitamin K2 for postmenopausal osteoporosis. Keio J Med 52, 147–50. 26 Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA (2010) Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 21 (6), 1041–5. 27 Theodore J, Hahn J (1993) Steroid and drug induced osteopenia. In: Favus MJ (ed) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 2nd edn, pp 250–2. Lipincott-Raven, Philadelphia, USA.
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SYSTEMATIC REVIEW
Treatment of glucocorticoid-induced low bone mineral density in children: a systematic review Arundathi JAYASENA,1 Navoda ATAPATTU1 and Sarath LEKAMWASAM2 1 Paediatric Endocrinology, Lady Ridgeway Hospital for Children, Colombo, and 2Department of Medicine, Faculty of Medicine, Centre for Metabolic Bone Diseases, Galle, Sri Lanka
Abstract Aims: The aim of this systematic review was to evaluate, critically, the treatment options used in the management of bone loss associated with glucocorticoid (GC) use among children. Methods: We performed a systematic search using PubMed, Cochrane clinical trial registry, Clinicaltiral.gov and Ovid databases (1 March, 2013). The search resulted in 34 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by two authors. Results: Four studies have compared the effectiveness of bisphosphonates in the treatment of GC-induced low bone mineral density (BMD) in children. Remaining studies were on menatretenone + alfacacidol versus alfacalcidol alone, calcium + vitamin D versus placebo and alfacalcidol versus menatetrenone. In the four studies, bisphosphonates have shown the ability either to improve BMD or prevent bone loss associated with GC use in children. However, alendronate either in oral or intravenous routes and oral pamidronate were the only bisphosphnates that have been studied in children. Vitamin K2 (menatetrenone) combined with alfacalcidol has also preserved BMD in children on long-term GC therapy. Calcium combined with alfacalcidol has also prevented bone loss, greater than menatetrenone. Calcitriol together with Calcium in conventional doses has retarded bone loss, although the combination could not completely prevent the process. Conclusions: Vitamin D derivatives such as calcitriol or alfacalcidol together with adequate calcium can be considered suitable treatment options to be started simultaneously when long-term GC therapy is needed in children. For children who have been on GCs or have already lost BMD, either oral pamidronate or alendronate in oral/intravenous routes can be considered based on the availability. Key words: children, bone mineral density, glucocorticiods.
INTRODUCTION Glucocorticoids (GCs) are widely used in pediatric practice. Long-term systemic GC therapy is associated with many side-effects, including low bone mineral density (BMD) and fragility fractures.1–3 Most studies examining the underlying mechanisms and pathophysiology
Correspondence: Professor Sarath Lekamwasam, MD, FRCP, PhD, Department of Medicine, Faculty of Medicine, Centre for Metabolic Bone Diseases, Galle, Sri Lanka. Email: [email protected]
of GC-induced bone loss have used adult subjects and studies among children are limited. The bone loss associated with GC use is rapid, initially, and continues as long as the drug is continued.2 The association between GC use and fractures among adults is well known. Van Staa et al. found baseline BMD to predict incident vertebral fractures among premenopausal women taking GCs. While each 1 unit decrease in T-score was associated with 1.85 relative risk of vertebral fracture (95% CI = 1.06–3.21), 10 mg increase of daily prednisolone dose was associated with a relative risk of 1.62 (95% CI = 1.11–2.36).4
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Y. A. Arundathi Jayasena et al.
In recent years, the issue of low bone density in children and adolescents has attracted much attention. GC-induced osteoporosis (GIO) in children is a very complex entity and it is further complicated by the limitations in available data. Furthermore, the current lively debate on the definition of osteoporosis in children, including GIO, illustrates the need for further research in this field. The diagnosis of osteoporosis during childhood and adolescence is based on the comparison of BMD with healthy subjects of the same age and sex, but the situation is compounded by the extensive inter-individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). Although BMD Z-score values below 2 and 1 are generally considered as osteoporosis and osteopenia, respectively, the diagnosis of osteoporosis in children and adolescents is only made in the presence of low BMD and at least one fragility fracture, by most specialists in the field. Due to the uncertainty of the definition, we prefer to use the term GC-induced low BMD (GC-LBMD) rather than osteoporosis or osteopenia when we address children in this review. However, for adults the term GIO is used in this review. Treatment of GC-LBMD in children is understudied and clinical trials involving children on GCs are sparse. Treatment options in GC-LBMD in children are greatly limited and management guidelines are not well established. The guidelines developed by the Royal Collage of Physicians, London in 2002 included only a brief account on children and the information given was not based on clinical trials.5 Similarly, American Rheumatology Council guidelines published in 2010 and Canadian guidelines published in 2002 do not address the issue of GC-LBMD management among children.6,7 The most recent framework provided to develop guidelines on GIO by the International Osteoporosis Foundation also did not consider subjects below 18 years of age.8 This leaves many children on GCs either untreated or partially treated. The situation is more critical in countries where screening facilities for low bone mass is restricted and general awareness of providing bone protection for patients on GCs is low. We conducted a systematic review on treatment of GC-LBMD in children based on the published literature acquired after a systematic search. The aim of the search was to critically evaluate the treatment options used in the treatment of GC-LBMD among children.
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METHOD The first search was conducted in the free-text version of PubMed using search terms ‘glucocorticoid* OR corticosteroid* OR steroid*’ AND ‘osteoporosis OR bone density OR fracture* OR height velocity’. The search was limited to the clinical trials and age below 18 years. The search was extended to the MeSH database using ‘glucocorticoids’ [Pharmacological Action] AND ‘Osteoporosis/chemically induced’ [Mesh] AND (Clinical Trial [ptyp] AND English [lang] AND (‘infant’ [MeSH Terms] OR ‘child’ [MeSH Terms] OR ‘adolescent’ [MeSH Terms])). We also used the ‘Clinical queries’ option of PubMed to trace relevant clinical trials. Apart from PubMed, Cochrane clinical trial registry, Clinicaltiral.gov and ovid databases were also searched using the appropriate search terms to retrieve the relevant literature. The search methodology we used is very similar to that used by the International Osteoporosis Foundation – European Calcified Tissue Society (IOF-ECTS) guidelines working group in 2012, when formulating a framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis.8 Two authors (AJ and SL) selected literature, blinded to each other, based on the following inclusion and exclusion criteria. Inclusion criteria were: systemic GCs, children below 18 years, clinical trials and outcome measures of bone mineral density, incidence of fractures or height velocity. Exclusion criteria were: patients on inhaled or topical steroids, methods other than clinical trials, outcome measure of biochemical markers and post-transplant recipients. Articles were categorized as ‘included’, ‘excluded’ and ‘doubtful’ by the two authors and the agreement between them was assessed. They decided on ‘doubtful’ articles by consensus. This process selected seven clinical trials on treatment of GC-induced low BMD in children. Data extracted were: age, underlying diseases, dose and duration of GC therapy, type of active treatment, care given to the control group, duration of study, change of outcome variables before and after treatment and the level of statistical significance.
RESULTS The PubMed search resulted in 36 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by the two
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authors.9–15 The kappa value for the agreement between two authors was 0.8. Searches in other databases did not yield any additional literature. The information related to baseline characteristics of subjects and type of care offered to the trial participants are summarized in Table 1. Changes in the outcome measures before and after treatment are shown in Table 2. All studies were clinical trials on patients of pediatric and adolescent age groups. The underlying diseases requiring GCs varied from autoimmune disorders to nephritic syndrome and nephropathy (Table 1). The duration of GC therapy also varied between the studies. In two of the studies drugs to prevent bone loss were started simultaneously with corticosteroid therapy,11,13 whereas in the remaining five clinical trials the efficacy of treatment was assessed in children who had received GCs for more than 3 months. Four studies9–11,14 compared the effectiveness of bisphosphonates in the treatment of GC-LBMD in children. Of these, two studies compared effectiveness of either intravenous (i.v.) or oral pamidronate over placebo.10,11 The other two studies assessed efficacy of intravenous alendronate9 or once weekly oral alendronate14 over placebo. The remaining studies were on menatetrenone + alfacacidol versus alfacalcidol alone,12 calcium + vitamin D versus placebo13 and alfacalcidol versus menatetrenone.15 The duration of clinical trials varied from 3 months to 2 years and sample size from 11 to 44 (Table 1). All included clinical trials used either change in absolute BMD Z-score or percentage BMD change as outcome variables (Table 2). Only two of the studies14,15 assessed height (Ht) velocity. None of the studies assessed the incidence of fractures during the follow-up period.
Effects of bisphosphonates Alendronate in i.v. and oral forms and oral pamidronate were effective in reducing bone loss associated with systemic GC therapy in children. In the study by Kim et al.11, oral pamidronate prevented BMD loss among treated subjects (mean BMD 0.644 and 0.647 before and after treatment) while the control group on calcium alone showed a significant decline in BMD (BMD 0.654 and 0.631 before and after treatment, P = 0.017). Although BMD changes were not explicitly shown, Inoue et al.9 observed similar results with intravenous alendronate. According to Rudge et al.14 once-weekly alendronate significantly increased the volumetric bone density of the lumbar spine (P = 0.013). The attempted randomized controlled trial with i.v.
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pamidronate by Brown and Zacharin10 did not show any significant treatment effect as a consequence of trial failure.
Other therapies Inoue et al. observed a 4.1% increase in BMD with i.v. menatretenone combined with alfacalcidol. Alfacalcidol alone given to the control group resulted in 1.3% decline in BMD.9 Authors concluded that i.v. menatretenone together with alfacalcidol is an effective treatment to prevent bone loss in children on GCs. However, Rianthavorn et al. showed that calcium supplementation along with alfacalcidol can prevent further bone loss to a greater extent than menatetrenone as the BMD Z-score ( 1.1 0.8 to 1.5 0.7 and 1.2 1.0 to 1.6 1.2 in menatetrenone and in alfacalcidol groups, respectively) at 12-month followup was significantly decreased from baseline in the menatetrenone group.15 Bak et al.13 found calcium and calcitriol retarded BMD loss among children receiving GCs (4.6% and 13.1% reduction in BMD with calcitriol + calcium and placebo, respectively). It is noteworthy that in the above trial, calcitriol and calcium were started simultaneously with GC therapy and it can be considered a prevention trial. However, the trial lasted only 8 weeks and lacks long-term follow-up BMD results.
DISCUSSION In this systematic review our aim was to analyze the available literature on treatment of GC-LBMD in children. We found only a very limited literature base and it did not allow us to assess the consistency of the results between studies. Furthermore, the trials included in this review have a restricted validity. When these trials were evaluated using the Jadad scoring system which is a standard scoring system to evaluate randomized controlled trials,16 the majority of them failed to gain a higher validity score. The Jadad score awards points for the acceptability of randomization as well as blinding and accounting for drop-outs. Many studies included in this analysis did not mention the method of randomization, blinding process or drop-outs. The attempted randomized controlled trial with i.v. pamidronate versus calcium and calcitriol by Brown and Zacharin10 illustrates the practical difficulties in conducting a randomized controlled trial in children due to unpredictable pattern of remissions and relapses, difficulty in getting consent and thus unacceptable drop-out rate. None of the studies have assessed the incidence of
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Rudge et al. (2005) Rianthavorn et al. (2012)
Inoue et al. (2001)
Kim and Cho (2006)
Inoue et al. (2008) Brown and Zacharin (2005) Bak et al. (2006)
Author/year
10
11
10
10
8
20
20
11
22
7
5
22
6
Control group
5
Study group
Sample size
Not specified
Chronic illnesses
Autoimmune diseases
Steroid-sensitive nephrotic syndrome Nephropathy
Autoimmune diseases Not specified
Underlying disease requiring glucocorticoid therapy
Alfacalcidol group 0.27 0.14 Menatetrenone group 0.31 0.17
0.1–2.4 mg/kg/day
Subjects 0.22 0.05
Intravenous pulse methylprednisolone+ oral prednisolone 1 mg/kg/day Controls 0.18 0.1
2
Minimum 18 months
Controls 33 15 months Subjects 37 13 months 0.3–7 years
Once weekly oral Alendronate Alfacalcidol + Calcium
Alfacalcidol + menatetrenone (vitamin K2)
Oral pamidronate + calcium
3 months (5 cycles)
1 year
1 year
12 weeks
3 months
8 weeks
Calcium + calcitriol
8 weeks
2 years
Duration of treatment
2 years
> 3 months
> 0.2
Type of treatment for glucocorticoid-induced low bone mineral density Intravenous alendronate + calcium + vitamin D Intravenous pamidronate
6 months
Duration
Not mentioned
Dose mg/kg/day
Glucocorticoid therapy
Table 1 Baseline characteristics and type of care received by trial participants
Menatetrenone + calcium
Oral placebo
Alfacalcidol
Oral calcium
Ca CO3 + vitamin D No treatment
No treatment
Care for control/ other group
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0.0029
< 0.001
1.3 2.4
3.0 4.0%
4.1 3.2
8.7 5.2%
< 0.01
0.0029 0.156
0.017
< 0.001
Rianthavorn et al. (2012)
Kim and Cho (2006) Inoue et al. (2001) Rudge et al. (2005)
BMD, bone mineral density
< 0.05
0.013
0.20 0.22 (Z-score) 0.52 0.18 to 0.45 0.16 g/cm2 0.654 0.069 to 0.631 0.070 g/cm2 0.704 0.147 g/cm2 0.255 0.013 to 0.276 0.011 g/cm3 Menatetrenone group 0.64 0.07 g/cm2 0.001
> 0.5
Not mentioned
0.03
0.04 0.48 0.57 (Z-score) 0.54 0.15 to 0.51 0.10 g/cm2 0.644 0.189 g/cm2 to 0.647 0.214 g/cm2 0.643 0.149 g/cm2 0.266 0.011 g/cm3 to 0.307 0.008 g/cm3 Alfacalcidol group 0.71 0.15 g/cm2
BMD
Not mentioned
Inoue et al. (2008) Brown and Zacharin (2005) Bak et al. (2006)
P-value Year
Subjects
P value
BMD
Controls Change in BMD Author/
Table 2 Changes in the outcome measures of the seven selected clinical trials
4.6 2.1%
6.6 4.0%
> 0.05
P-value between groups Controls BMD P between groups
Subjects BMD
Percentage change in BMD
Glucocorticoid-induced low BMD in children
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fractures which is an important clinical measure of bone metabolism in children. Only two of the studies14,15 have assessed Ht velocity. Limited information from this review reveals that bisphosphonates are effective in the treatment of GCLBMD in children. However, alendronate and pamidronate are the only bisphosphnates that have been studied in children so far. Pamidronate in oral form is shown to be effective but the effectiveness of the i.v. form which is widely used in clinical practice remains unknown. Vitamin K2 (menatetrenone) with alfacalcidol has also preserved BMD in children on long-term GC therapy. However, calcium supplementation along with alfacalcidol can prevent further bone loss to a greater extent than menatetrenone. Calcitriol together with calcium in conventional doses appears to retard bone loss although the combination does not completely prevent the process. The possible retardation of bone loss with vitamin D derivatives was evident in the Inoue et al.9 study as well. In this study, the control group who were given alfacalcidol lost BMD only by 1.3%. Meta-analyses have consistently shown that bisphosphonates are effective in the prevention and treatment of GIO among adults.6,17,18 Several studies have reported the efficacy of vitamin K2/menatetrenone in the treatment of GIO, adult form, in Japan.19,20 Vitamin K2/menatetrenone along with vitamin D3 appear to have a protective effect on lumbar BMD in GIO.21,22 Furthermore, vitamin K2 is shown to have a preventive effect on occurrence of new fractures in osteoporosis.23– 25 Thus the findings of Inoue et al. are comparable with the existing data in the adult population, although latest evidence from Rianthavorn et al.15 show that alfacalcidol can prevent further bone loss to a greater extent than menatetrenone. Nevertheless menatetrenone lacks approval for the treatment of osteoporosis in any part of the world and also is not included in any management guidelines related to osteoporosis. However, only two bisphosphonates, namely alendronate and pamidronate have been studied in children up to now. The other bisphosphontes approved to treat adult GIO such as oral risedronate and i.v. zoledronic acid and newer therapeutic modalities such as teriparatide have not been studied in children so far. However, the possible carcinogenicity of teriparatide exposure, especially in children, needs to be seriously considered.26 Bone mineral loss associated with GC therapy appears to be a result of direct suppression of osteoblastic bone-forming activity and increased bone resorption
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caused by parathyroid hormone stimulation of osteoclastic activity.26 Bone loss is more pronounced in regions with high content of trabecular bone such as vertebrae, ribs and ends of long bones. In younger individuals, the high rate of bone turnover predisposes to more rapid bone loss.27 Recent data indicates that a rapid loss of bone occurs immediately after the initiation of GC therapy with 10–20% or more loss of trabecular mass occurring over the first 3–6 months.2 Furthermore, diverse effects of GC therapy on body weight, growth velocity and sexual maturation in children may contribute to the acquisition of peak bone mass and future fracture risk. The extent of recovery of growth velocity and bone mass in children after the termination of GC therapy is unknown.2 Although alendronate and pamidronate have been shown to be effective in the treatment of GC-LBMD in children, follow-up studies regarding efficacy, safety and side-effects need to be done. Bisphosphonates in general have many adverse effects and safety concerns. Apart from the well-known upper gastrointestinal sideeffects, the long-term retention of the drug in the body may create problems for young women in the reproductive age when planning pregnancy. Current data is not sufficient to determine whether long-term bisphosphonate therapy has any adverse outcome on the skeletal growth of adolescent children. The long-term growth velocity and fracture risk are more clinically relevant outcome measures and the effect of such therapies on these outcome measures need to be assessed in children on long-term GC therapy. Furthermore, the necessity of proper randomized controlled trials with high validity on newer bisphophonates and other therapeutic modalities such as teriparatide is evident. Until such data are available, clinicians involved in the management of children on long-term GC therapy have limited therapeutic options. Vitamin D derivatives such as calcitriol or alfacalcidol can be considered suitable treatment options to be started simultaneously when long-term GC therapy is needed. For children who have been on GCs, either oral pamidronate or alendronate in oral and i.v. form can be considered based on availability. Although vitamin K especially in combination with vitamin D has prevented bone loss, such therapy cannot be recommended as it lacks Food and Drug Administration approval for the treatment of GIO in adults. Apart from co-prescribing drugs to prevent GCinduced bone loss, clinicians should attempt reducing the dose of GC or completely withdraw them whenever possible. Other measures such as alternate day
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treatment and use of other routes to administer GCs should be considered. The long-term adverse effects of the prophylactic medications discussed above also need to be addressed. While the long-term safety of many drugs has not been adequately assessed, hypercalcemia and hypercalciuria are well-known unwanted effects of vitamin D derivatives.
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