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NIHR Health Technology Assessment programme: Executive Summaries.

A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management

J Thornton, D Ashcroft, T O'Neill, R Elliott, J Adams, C Roberts, M Rooney, and D Symmons.

Author Information

Published: 2008.

Background

Low bone mineral density (BMD) and fragility fractures are serious complications of juvenile idiopathic arthritis (JIA), but evidence from strategies for prevention and treatment has not been evaluated. The original aim of this project was to undertake a cost-effectiveness analysis of the lifetime fracture risk of children with JIA. We reviewed methods of assessing bone health in children with JIA, including quantitative imaging techniques, biochemical markers of bone turnover and fractures, to assess the available evidence and to assess the strengths and limitations of each method. We then undertook a systematic review of (1) the evidence for effectiveness of bisphosphonates and calcium and/or vitamin D in children with JIA and (2) the costs of treating children with JIA and low BMD and/or fragility fractures. During this study, it became clear that the data are not available for a health technology assessment of interventions to prevent and manageosteoporosis in JIA that complies with these criteria. Key omissions are: the lack of comparative effectiveness data, the limitations of outcomes in that they do not assess all health effects on individuals and measurement of quality-adjusted life-years has not been carried out, the lack of prospective resource use and cost data in the appropriate patient group. Therefore, to produce some evidence as useful background for future research in this area, we estimated the lifetime risk of low BMD and fractures from two cohorts of adults with JIA and conducted a cost analysis of the management of JIA for 1 year from diagnosis.

Objectives

The objectives were as follows:

  • to review outcome measures in children with JIA and low BMD and/or fragility fractures
  • to review evidence for effectiveness and safety of bisphosphonates and calcium and/or vitamin D in these children
  • to assess long-term bone health in adults with JIA
  • to review costs of treating children with JIA and low BMD and/or fragility fractures
  • to evaluate the cost of treating JIA.

Review of outcome measures

Low BMD in childhood JIA is a function of current growth and the morbidity caused by JIA; the combination of these factors complicates the assessment of bone health in these children. It is necessary to distinguish disease-related changes from natural growth and development in order to determine the effects of JIA and its treatment. The review question for this part of the report is as follows: in children with JIA, how effective are patient-based outcome measures, quantitative imaging techniques, biochemical markers of bone turnover and fractures for assessing bone health?

Methods

Electronic searches were undertaken (up to July 2006) together with checking of bibliographies of papers. Studies describing (1) patient-based outcome measures, (2) quantitative imaging measures: dual-energy photon absorptiometry (DXA), quantitative computed tomography (QCT), quantitative ultrasound (QUS) and digital X-ray radiogrammetry (DXR), (3) biochemical markers of bone turnover and (4) fractures, to assess bone health in children with JIA were included.

Results

Two studies evaluated the use of patient-based outcome measures in children with JIA and low BMD; one study found a correlation between BMD and Childhood Health Assessment Questionnaire score but the second found no correlation with Juvenile Arthritis Functional Assessment Report score. In the review of quantitative imaging techniques, DXA (25 studies) was sensitive to differences between different subtypes of JIA, disease severity and factors such as treatment with corticosteroids and could distinguish between children with JIA and healthy control children. However, DXA results in children must be interpreted with care because of technical issues. One study using QCT and one using peripheral QCT in JIA were identified and data were insufficient to assess the usefulness of this technique. However, QCT provides a true volumetric density but scanning equipment is harder to access and doses of radiation are relatively high. Seven studies used QUS and showed that ultrasound could distinguish between children with JIA and healthy children and that there was correlation between ultrasound parameters and BMD from DXA. QUS is a promising technique that does not expose children to radiation, but there are limited data in children. Eighteen studies examined biochemical markers of bone turnover. In some studies, levels of osteocalcin, alkaline phosphatase, hydroxyproline, tartrate-resistant acid phosphatase, procollagen type I C-propeptide, C-terminal cross-linked telopeptide of type I collagen and deoxypyridinoline were changed in children with JIA compared with healthy children; in other studies, the levels were unchanged. Similarly, results from studies in children with different severities of disease were not consistent. Only two studies described the use of fractures as outcome measures. One study recorded an increase in spinal fractures in children with JIA who had started early treatment with corticosteroids compared with those who started treatment later. The second study noted four fractures during 18 months of follow-up.

Systematic review of effectiveness of bisphosphonate and calcium and/or vitamin D

We reviewed the safety and effectiveness of interventions for the prevention and/or treatment of low BMD and fragility fractures in children with JIA.

Methods

Electronic searches were undertaken (up to July 2005), together with checking of bibliographies of papers. Studies of bisphosphonates and calcium and/or vitamin D in children with JIA were included. Reports from children with osteogenesisimperfecta (OI) were also included in the review of safety.

Results

Because of the sparsity of data, we adopted a pragmatic approach and included all study designs, case series and case reports in the review of bisphosphonate treatment. Sixteen studies (78 JIA children) were included: one randomised controlled trial (RCT), three controlled cohort studies, 11 case series, and one case report. At baseline, children had BMD below the expected values for age- and sex-matched children; treatment with bisphosphonates increased BMD with mean percentage increases in spine BMD varying from 4.5 to 19.1%. None of the studies with control groups compared results between the intervention and control groups; they only compared each group with its own baseline. In the RCT, spine bone mineral apparent density increased significantly from baseline in the alendronate-treated group (0.266 to 0.307, p = 0.013), whereas there was little change in the placebo-treated group (0.255 to 0.276, p = 0.156). Overall, studies were heterogeneous in design, of variable quality and with no consistency in methods of assessing and reporting outcomes. Hence, data could not be combined or an effect size calculated. A further 43 papers were included in the safety review; side-effects were generally transient. Two studies assessed treatment with calcium and/or vitamin D; BMD was increased from 0.75 to 0.830 g/cm2 after 6 months and BMD Z-score from –2.8 to –2.3 after 6 months and –2.4 after 1 year.

Evaluation of long-term bone health

The objective of this part of the study was to describe the long-term occurrence of fractures in adults with JIA and compare with that expected in the general population of healthy adults. Long-term outcome data were derived from two cohorts of adult patients with JIA.

Results

Large longitudinal studies using the General Practice Research Database provide age-related data on the occurrence of fragility fractures in adults and children. The relationship between low bone mass and increased risk of fractures in postmenopausal women is well recognised but there also appears to be an association between low BMD and fractures in children. There are relatively few long-term studies on the occurrence of low BMD and fragility fractures in children with JIA, with most studies only following children for 1 or 2 years. However, the long- and short-term data indicate that children with JIA have a lower BMD and more fractures than children without JIA. There are very few data on long-term bone health from adults who have JIA but studies indicate that low BMD persists into adulthood, although adults in remission from JIA may attain the same BMD as healthy adults. From the available data, any predictors of low BMD and fractures in children and adults with JIA remain uncertain.

Systematic review of costs

No studies discussed the costs of treating children with JIA and low BMD and/or fragility fractures.

Evaluation of costs of treating JIA

Because the published clinical effectiveness and cost data for the treatment of children with JIA and low BMD and/or fragility fractures are limited, it was not possible to undertake economic modelling. Therefore, as a starting point, the aim of this part of the study was to evaluate the overall cost of treating children with JIA. We analysed costs from an ongoing UK longitudinal study within the University of Manchester Arthritis Research Campaign (arc) Epidemiology Unit: Childhood Arthritis Prospective Study (CAPS). This study was not designed to study bone health specifically but the analysis provided background data on the cost of managing JIA.

Methods

Children with newly diagnosed inflammatory arthritis of one or more joints, which has persisted for at least 2 weeks, are recruited to CAPS. Data are collected at study entry, 6 months and 1 year: children undergo a rheumatological examination by the consultant and assessment by the nurse, and a comprehensive case notes review is undertaken. Health service resource use data (appointments with paediatric consultant rheumatologist, referrals to other healthcare professionals, drugs, laboratory tests and clinical imaging) were extracted, unit costs applied and the cost of management calculated.

Results

A total of 457 children with JIA have been recruited and 297 of these attended a 12-month follow-up visit. The mean annual total cost per child in the first year after diagnosis was £1649 (standard deviation £1093, range £401–6967). The highest cost component was appointments with paediatric rheumatologists. The study is continuing to accrue and follow up patients and further analyses will be undertaken as the study progresses.

Conclusions

Assessment of outcome measures relating to bone health in children with JIA

BMD, adjusted for size, should be assessed as the primary outcome in studies of bone health in children with JIA. QCT could be used where equipment is available as it offers the advantage of measuring volumetric density. Other outcome measures may also be useful but further data are needed to establish their role.

Systematic review of effectiveness of bisphosphonate and calcium and/or vitamin D

Bisphosphonates are a promising treatment for osteoporosis in children with JIA, but the quality of the current evidence is poor. Better studies are needed to assess more clearly their role and permit licensing of these agents for treatment of children. In particular, longer-term studies are needed to evaluate the effectiveness and safety of this treatment into adulthood. The accurate assessment of outcome is crucial.

There are still uncertainties about the use of bisphosphonates in children, including whether the positive effects of treatment continue over time, the length of treatment and the maximal bone mass gain that can be achieved. In particular, longer-term studies are needed to evaluate the effectiveness and safety of this treatment into adulthood.

Long-term bone health in JIA

Adults with JIA may have persistent low BMD compared with an otherwise healthy population together with an increased risk of fracture.

Systematic review of costs for managing children with JIA and low BMD or fragility fractures

There are no studies evaluating the costs of treating children with JIA and low BMD and/or fragility fractures. There are few data evaluating the costs of treating JIA in general.

Assessment of cost of treatment for JIA

In the first 12 months after diagnosis, children with all JIA disease subtypes consume large, but highly variable, quantities of health service resources. The largest component of health provider costs was consultant rheumatology appointments.

The right-skewed distribution of costs suggests that a few high cost outliers increased the mean costs for the group overall, and within individual disease subgroups. Data from a larger cohort, over a longer period, are required to substantiate these results further.

Implications for healthcare

All methods of assessing outcome have limitations; DXA is the current most practical measure but results in children must be interpreted with care. Fractures would be the ideal outcome measure but a study with this end-point would require large numbers of patients and long-term follow up. However, fracture data could be routinely collected for local and other registers. Bisphosphonates seem to be effective in the management of children with JIA but the evidence is limited. Few children with JIA have been treated with bisphosphonates; the studies include case series and case reports and there are no true controlled studies, the studies are heterogeneic in design (different subtypes of JIA are included in different studies, children with other connective tissue disease also included, different bisphosphonates and varied doses and routes of administration are used and durations of treatment and follow-up times vary), together with poor assessment of outcome measures and varied methods of reporting results. There are still many unanswered questions about bisphosphonates' use, including the optimum dose and frequency of administration and length of treatment. The maximal BMD gain that can be achieved is not known. It is not clear whether the positive effects of treatment continue over time. There is limited evidence on the use of calcium and/or vitamin D. Assessment of outcome was poor in all studies. The problems of poor bone health persist into adulthood; adults with JIA have an increased numbers of fractures compared with expected values in otherwise healthy adults.

Recommendations for research

Areas for further research are as follows:

  • The arc has initiated an RCT of bisphosphonates and 1-α-hydroxycholecalciferol (hydroxylated derivative of vitamin D) in children with JIA. This study should address some of the research issues raised in this report.
  • Longer-term follow-up of studies with bisphosphonates and calcium and/or vitamin D is needed to determine the longer-term effect of treatment on both bone mass and fracture risk, and also safety.
  • A cohort study of children with newly diagnosed JIA should examine the effects of disease and current management approaches on bone health in these children.
  • Large prospective studies are needed to determine the predictors of bone mass and fractures in adults with JIA.
  • Longitudinal studies of DXA should be conducted to consider whether bone mass measured by DXA predicts bone mass and fracture risk in adults.
  • Most current evidence relates to the use of DXA for assessing bone health in children. Further evaluation of other quantitative imaging techniques is required.
  • More studies are needed looking at the performance of biochemical markers in children with JIA. The effect of treatment on markers in children with JIA should be assessed.
  • An HRQoL measure should be validated specifically for use in children with low trauma fractures.
  • Future studies should examine costs of management of bone health in JIA in both the short and medium term. A cost-effectiveness or cost–utility evaluation could be incorporated. Future studies examining bone health in children should have an economic component.

Publication

  • Thornton J, Ashcroft D, O'Neill T, Elliott R, Adams J, Roberts C, et al. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management. Health Technol Assess 2008;12(3). [PubMed: 18284894]

NIHR Health Technology Assessment Programme

The Health Technology Assessment (HTA) Programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

The research findings from the HTA Programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the 'National Knowledge Service'.

The HTA Programme is needs-led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects.

First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, the public and consumer groups and professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA Programme then commissions the research by competitive tender.

Secondly, the HTA Programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour.

Thirdly, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies.

Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem.

The final reports from HTA projects are peer-reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment.

Criteria for inclusion in the HTA journal series

Reports are published in the HTA journal series if (1) they have resulted from work for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.

Reviews in Health Technology Assessment are termed 'systematic' when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the journal was commissioned by the HTA Programme as project number 03/43/04. The contractual start date was in November 2004. The draft report began editorial review in July 2006 and was accepted for publication in July 2007. As the funder, by devising a commissioning brief, the HTA Programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.

Editor-in-Chief: Professor Tom Walley

Series Editors: Dr Aileen Clarke, Dr Peter Davidson, Dr Chris Hyde, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein

Programme Managers: Sarah Llewellyn Lloyd, Stephen Lemon, Kate Rodger, Stephanie Russell and Pauline Swinburne

© 2008 Crown Copyright.

Included under terms of UK Non-commercial Government License.

PMID: 18284894

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