Chapter 7: Osteoporosis in Children

OSTEOPOROSIS
Systematic literature search to December 2000 plus some key references from 20

7: Osteoporosis in Children

It should be remembered that the World Health Organisation criteria for osteoporosis and osteopenia were developed for women and may or may not apply to children. Risk and preventive factors for low bone mass and osteoporosis in children are considered in Chapter 1.
7a. Corticosteroid use is a well known cause of osteoporosis in children. High dose methotrexate (such as used for childhood leukaemia) causes osteopathy in children and cyclosporine has been shown to cause a high turnover osteopenia. Active arthritis has osteopenic effects around affected joints and decreases bone density away from affected jointsⁱ.	i. Rabinovich CE. Bone mineral status in juvenile rheumatoid arthritis. Journal of Rheumatology 2000; 27(suppl.58): 34-37 (Type V evidence – expert opinion based on a review of the evidence)
7b. At diagnosis of childhood malignancy, there were no differences in BMD compared to healthy age- and gender-matched controls. However, increased bone resorption and decreased bone formation was already present. The negative balance in bone turnover decreased throughout the follow-up and a reduction in BMD was observed 6 months after diagnosis. No independent correlation was found between the reduction in BMD and corticosteroid therapy or any of the antineoplastic agentsⁱ.	i. Arikoski P, Komulainen J, Riikonen P et al. Impaired development of bone mineral density during chemotherapy: A prospective analysis of 46 children newly diagnosed with cancer. Journal of Bone and Mineral Research 1999; 14(12): 2002-2009 (Type IV evidence – bone mass (by dual energy x-ray absorptiometry) and turnover measurement in 46 children (age 2.9-16, median 8 years. 15 leukaemias, 12 lymphomas & 19 solid tumours). Measurements were made at diagnosis and after 6 months from baseline)
7c. The cause of idiopathic juvenile osteoporosis is unknown. The basic strategy of treatment is to protect the spine until remission occurs. Sex steroids are contraindicated. Bisphosphonates, calcitriol, fluoride and calcitonin have been administered therapeutically but the results were equivocal. Usually the disease remits by itselfⁱ.	i. Krassas GE. Idiopathic juvenile osteoporosis. Annals of the New York Academy of Sciences 2000; 900: 409-412 (Type V evidence – expert opinion) Top
7d. Speed of sound (SOS) shows a significant correlation with BMD as measured by DXA, albeit with wide 95% confidence intervals in a small pilot study. Quantitative ultrasound (QUS) was also well tolerated and was technically easy to perform. With the added advantage that it is free from radiation risk, further assessment of this potentially valuable tool for measuring bone status in children is warrantedⁱ. See also Chapter 2 for a consideration of DXA versus ultrasound in adults.	i. Njeh CF, Shaw N, Gardner-Medwin JM, Boivin CM, Southwood TR. Use of quantitative ultrasound to assess bone status in children with juvenile idiopathic arthritis: a pilot study. Journal of Clinical Densitometry 2000; 3(3): 251-260 (Type IV evidence – pilot study to compare QUS with DXA in 22 caucasian children with juvenile idiopathic arthritis of duration 19-142 months (mean 71 months) and age 7-17 years)
7e. There is evidence that some children with rheumatic disease receiving corticosteroids would benefit from calcium and vitamin D supplementation. During supplementation, of nine patients who completed all the BMD measurements, the mean spinal BMD increased to 11% over the baseline measures. Eight patients had increased BMD and one had decreased BMD. Seven patients had lower BMD values without supplementation, two had improved valuesⁱ. Calcitriol has also been used in idiopathic juvenile osteoporosis with improvement in symptoms, fracture frequency and bone mineral content. Follow-up at 6 and 12 months showed a significant increase in bone mineralisation, which reached normal values in two children after 12 months of treatment. The untreated patient did not show an improvement of bone mineralisation in the same timeⁱⁱ. Although there is little evidence that calcium and vitamin D supplementation is of benefit in childhood osteoporosis, it is recommended that such children should receive an adequate calcium intake(see Statement 1.2e).	i. Warady BD, Lindsley CB, Robinson RG, Lukert BP. Effects of nutritional supplementation on bone mineral status of children with rheumatic diseases receiving corticosteroid therapy. Journal of Rheumatology 1994; 21(3): 530-535 (Type IV evidence – case series, using a cross-over design, of 10 corticosteroid treated children with rheumatic disease and osteoporosis receiving 6 months supplementary calcium and vitamin D (to supply a minimum of 1 g calcium and 400 IU vitamin D daily) and 6 months without supplementation ii. Saggese G, Bertelloni S, Baroncelli GI, Perri G, Calderazzi A. Mineral metabolism and calcitriol therapy in idiopathic juvenile osteoporosis. American Journal of Diseases of Childhood 1991; 145: 457-462 (Type IV evidence – case studies of four children ranging in age from 2.3 to 12.6. Three children were treated with calcitriol (1,25—dihydroxycholecalciferol) (0.50 microg/day in two and 0.25 microg/day in the other). The fourth patient was not treated because of parental refusal) Top
7f. Alendronate has a positive effect on secondary osteopenia/osteoporosis in children with connective tissue diseases. BMD increased by a mean ± SD of 14.9 ± 9.8% (p<0.002 versus baseline) in the treated patients (reaching the normal range in 13 patients), while the BMD was 2.6 ± 5% (not significant versus baseline) in the control group (15 had a decrease). There was a large increase in BMD (15.3 ± 9.9%) after alendronate therapy in the 16 children who had their BMD followed up in the year before the study, during which time they had shown little increase in BMD (1.03 ± 6.3%), and often a decrease. No new fractures were observed after alendronate therapy was initiatedⁱ.	i. Bianchi ML, Cimaz R, Bardare M et al. Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: A prospective multicenter study. Arthritis & Rheumatism 2000; 43(9): 1960-1966 (Type III evidence – controlled study of 38 children with low bone mass treated with alendronate (5 mg/day for a body weight of ≤20 kg; 10 mg/day for >20 kg). 38 children who had the same primary disorders as the study patients but in a less severe form, served as untreated control patients)
7g. Intravenous pamidronate appears to be a useful therapeutic option in childhood osteoporosis, but its use in children must still be regarded as experimental and therefore closely monitored. Each child had rapid pain relief following the first treatment, followed by large increments in lumbar spine bone density over one year (%increments of 26%-54% as compared to the expected increases due to growth of 3%-15%)ⁱ. Caveat: This is not a licensed indication. Oral pamidronate is not used anymore and is not available.	i. Shaw NJ, Boivin CM, Crabtree NJ. Intravenous pamidronate in juvenile osteoporosis. Archives of Disease in Childhood 2000; 83(2): 143-145 (Type IV evidence – case studies of five children with vertebral osteoporosis who developed compression fratures in the thoracic and/or lumbar spine as a consequence of five different conditions. Children received treatment with intravenous pamidronate in doses ranging from 0.5-12 mg/kg/year) Top
7h. In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption and increased bone density. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (p<0.001) but treatment did not alter the rate of fracture healing, the growth rate or the appearance of growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All children reported substantial relief of chronic pain and fatigue. 26 children experienced an ‘acute-phase reaction’ on the second day of the first infusion cycle; this was controlled with acetaminophen and did not recur during subsequent treatment cyclesⁱ.	i. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. New England Journal of Medicine 1998; 339: 947-952 (Type IV evidence – uncontrolled observational study of 30 children (aged 3-16) with severe osteogenesis imperfecta. Pamidronate was administered intravenously (mean [± SD] dose, 6.8±1.1 mg/kg body weight per year) at 4- to 6-month intervals for 1.3 to 5.0 years. Calcium intake was maintained at 800-1000 mg/day and vitamin D intake was at least 400 IU/day)
7i. Bisphosphonates offer the pediatrician a new tool to treat children with primary and secondary metabolic diseases associated with increased bone resorptionⁱ and their use in paediatrics is sure to increaseⁱⁱ. As more children receive these drugs for an expanding range of conditions, very detailed patient monitoring is critical and these children should be followed up by paediatricians with a special interest in growth and skeletal diseaseⁱⁱ. The theoretical concerns of growth impairment from bisphosphonates have not been observed in the reported literature but there is a need to perform more placebo-controlled clinical trialsⁱ.	i. Srivastava T, Alon US. Bisphosphonates: From grandparents to grandchildren. Clinical Pediatrics 1999; 38: 687-702 (Type V evidence – expert opinion based on a critical review of 24 paediatric case-series and case-studies looking at various conditions and bisphosphonate therapies. 110 cases in all) ii. Shoemaker LR. Expanding role of bisphosphonate therapy in children. Journal of Pediatrics 1999; 134: 264-267 (Type V evidence – expert review of the literature) Top
7j. Based on evidence of increased growth rate versus some reported increased fracture rate, growth hormone should probably not be used as first-line therapy in osteogenesis imperfecta, pending further data from clinical trials. Growth hormone for idiopathic juvenile osteoporosis (which appears to improve naturally during puberty) should currently be used only in research and not in clinical practiceⁱ.	i. Wright NM. Just taller or more bone? The impact of growth hormone on osteogenesis imperfecta and idiopathic juvenile osteoporosis. Journal of Pediatric Endocrinology and Metabolism 2000; 13: 999-1002 (Type V evidence – expert review of three clinical trials (aggregate study population, 46) and 13 patient reports on osteogenesis imperfecta. No published reports were found on idiopathic juvenile osteoporosis)
7k. Growth hormone might be a useful adjunct in the treatment of severe growth retardation and osteoporosis in children with juvenile chronic arthritis. The longterm benefits of rhGH in the treatment of osteoporosis remain unclearⁱ. Caveat: Small and inconclusive study with a number of potential confounders (for example, the control group used was from another study).	i. Rooney M, Davies UM, Reeve J, Preece M, Ansell BM, Woo PMM. Bone mineral content and bone mineral metabolism: changes after growth hormone treatment in juvenile chronic arthritis. Journal of Rheumatology 2000; 27(4): 1073-1081 (Type III evidence – bone mineral content measurement in 20 children (of whom 17 were treated with corticosteroid) before and after one year of rhGH. Children were randomised to receive either low dose (12 IU/m²/week) or high dose (24 IU/m²/week) rhGH. A non-treatment comparison group was used from another study)

Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk