Evidence from the studies included in this review indicates that bisphosphonates may have a role in preventing low BMD and fragility fractures associated with JIA. However, the quality of the studies was variable. Only small numbers of children with JIA were included and studies recruited a mixture of children with JIA and other connective tissue diseases. Only one study reported that they used a standard definition of JIA.21
There was considerable variation in the doses and schedules of bisphosphonates. Some children had been treated with corticosteroids when they entered the study and continued with treatment, others were not. It is possible that concomitant treatment with calcium and/or vitamin D may have affected the outcome, but only nine studies ensured that the children received an adequate calcium and/or vitamin D intake.
Four studies included an intervention group of children treated with bisphosphonates and a control group of children receiving standard treatment.20,21,22,23
However, none of the studies compared directly the results of intervention and control groups; the results were only compared with the group's own baseline. There were also differences in disease severity between groups. Acott et al
compared corticosteroid treated children who had experienced fractures with corticosteroid treated children who had not experienced fractures and had greater BMD.23
Similarly, the control group of children recruited by Bianchi et al
had less severe disease which did not require corticosteroid therapy and had not experienced fragility fractures.21
The current methods of assessment of treatment outcome all have limitations. Measurement of BMD using DXA was the most widely used outcome measure in these studies but careful interpretation of the results is required.78
DXA estimates BMD as a two‐dimensional ratio of the amount of bone and the area scanned (aBMD) rather than true three‐dimensional density. aBMD increases with bone size because of the greater thickness of larger bones; it underestimates aBMD in small children and overestimates it in larger children and thus may be affected by the child's body size, pubertal stage, and, to a lesser extent, age and ethnic group.78
Several methods are available to adjust aBMD to account for the size of children.78
The observed increase in aBMD after treatment with bisphosphonates may, in part, be caused by changes in bone size related to growth and puberty, but only two studies in the review reported that they adjusted BMD for size,19,21
while two estimated volumetric BMD.20,25
The fact that adjustments may not have been made to account for the size of children undermines the validity of the results and makes it difficult to compare results between studies.
Eight studies examined biochemical markers of bone turnover and noted changes in levels during treatment. However, there is uncertainty about which markers best reflect bone status. In addition, few normative data are available for paediatric bone markers which are affected by age, sex, and puberty.
Both densitometry and bone markers are surrogate outcomes; the outcome of main interest and significance is reduction in fracture occurrence in the subjects as both children and adults. Although only short term studies have been conducted, several showed a reduction in fractures during treatment with bisphosphonates. Longer term studies are needed to show that these effects are sustained.
The review of safety showed that bisphosphonates were generally well tolerated in children. However, there is a report of iatrogenic osteopetrosis after administration of very high doses of intravenous pamidronate for “idiopathic hyperphosphatasia”.79
A major concern has been about long term effects. Although bisphosphonates have anti‐resorptive effects on bone, there was no evidence of adverse long term effects at commonly used doses. Hoekman et al
observed that all the biochemical markers of bone turnover returned to pretreatment levels after stopping bisphosphonate treatment, suggesting that there was no permanent inhibition of bone activity.80
Several studies reported that fracture and osteotomy site healing was not delayed. Linear growth was unaffected by treatment. Sclerotic lines have occurred but they faded or disappeared, although a recently published study shows that they can persist for up to 8 years (mean 4 years).81
This study also noted that pamidronate interferes with the process of periosteal resorption, resulting in wider metaphyses.81
There have been concerns that bisphosphonates could be retained in bone then released later in life. Of note, two young women continued treatment with bisphosphonate until conception without untoward effects on themselves or their babies.66
However, because of the different disease pathologies, some care should be taken with the extrapolation of results from the use of bisphosphonates in osteogenesis imperfecta to effects in children with JIA. For example, there are anecdotal reports of bone mineral density increasing with bisphosphonates, but after prolonged treatment the bones were found to be more brittle during spinal surgery.82
There is also concern that bisphosphonates administered at higher doses produce highly mineralised bone that is subject to microfracture damage,83
which might potentially increase the risk of cortical fractures in the long term. The effects of long term accumulation of bisphosphonates in children are unknown.
In conclusion, bisphosphonates are a promising treatment for osteoporosis in children with JIA, but the quality of the current evidence is variable; better studies are needed to support evidence based practice in this patient group. The lack of evidence in this area reflects a wider gap in evidence available to support paediatric prescribing. The recent National Service Framework for Children recommends that children who require ongoing health interventions have access to high quality care.84
This access is reduced by the lack of evidence to support prescribers in providing safe and effective treatments. Recognition of this gap has led to the development of the Medicines for Children Research Network which aims to improve the quality of research in this area (http://www.liv.ac.uk/mcrn/
). Studies need to recruit larger numbers of more clearly defined patients. Outcome must be accurately assessed, taking into account both growth of children during the study and any technical limitations of the measures. A recent general review supports our findings that there are still many unanswered questions about the use of bisphosphonates in children.16
The optimum dose and frequency of administration and the length of treatment have not been defined. The maximal bone mass gain that can be achieved is not known and it is not clear whether the positive effects of treatment continue over time. The criteria for initiating treatment need clarifying; should treatment be limited to children with pre‐existing low BMD and/or fractures or include children thought to be at risk of these problems? Finally, future studies should be longer term and include fragility fractures as an outcome. Multicentre studies are more likely to achieve sufficient patient numbers to answer some of these questions about longer term treatment, including the change in fracture incidence.
Finally, more aggressive treatment of JIA with intra‐articular corticosteroids and intravenous corticosteroid pulses may help avoid long term treatment with oral corticosteroids. In addition, increased and earlier use of disease modifying antirheumatic drugs such as methotrexate and cytokine inhibitors such as etanercept and infliximab might reduce the decline in BMD in these children.