As far as we know, our study is the first to examine population based fracture risk in a large cohort of subjects with childhood arthritis. We demonstrated a significantly increased fracture risk in subjects with arthritis that was most pronounced during the adolescent years, when fractures are common occurrences, and after the age of 45 years, when bone mass begins to decline. The IRR for first fracture among children aged <10 years and adults between 20 and 45 years of age at the start of follow up suggested an increased fracture risk of 49% and 40%, respectively, but this did not achieve statistical significance. Fractures were more common in subjects with arthritis at clinically significant sites, such as the humerus, forearm, femur, and lower leg. The fracture risk estimates were robust in sensitivity analyses designed to maximise the specificity of the arthritis group. The sex distribution of subjects with arthritis in the sensitivity analyses was consistent with that seen in the tertiary care setting.29
The increased risks for fracture observed in this study are comparable to those seen in other high risk groups.16,17,18,20,30,31,32,33
For example, van Staa et al
found that patients with inflammatory bowel disease have a 59% increase in hip fracture risk.16
In addition, because of the high rates of fractures among children in general, even modest relative risks translate into large risk differences.
About one third of children have a fracture. Using the GPRD, Cooper et al
found that fractures are more common in boys, particularly around the time of puberty.27
Peak fracture incidence occurred at 13–15 years in boys and 10–12 years in girls. Their estimates of forearm fracture incidence were similar to those in a study by Khosla et al
which attests to the generalisability of our findings to populations outside the United Kingdom. Our study is strengthened by the use of the same fracture codes as those used by Cooper et al
(van Staa TP, personal communication).
Throughout growth, increases in bone density and dimensions result in increased bone strength. The risk of fracture seems to be dependent on these structural determinants of bone integrity. Goulding and colleagues demonstrated that children with forearm fractures had lower dual x
ray absorptiometry (DXA) derived bone mass than controls.34,35
In a pQCT study examining girls with forearm fractures, Skaggs et al
found that despite similar cortical and trabecular density, the cross sectional area of the radius was 8% lower in the fracture group, consistent with diminished bone strength.36
Recent studies in children with JIA have demonstrated variable bone deficits,6
possibly related to differences among arthritis groups, suboptimal control populations, and challenges in the analysis and interpretation of DXA and pQCT results. In general, studies have been limited by the confounding effect of short stature on DXA estimates of bone health. pQCT derived trabecular volumetric density is thought to be less susceptible to confounding by skeletal size, and the precise measurement of cortical dimensions allows for an assessment of bone strength. Roth et al
examined children with active JIA and found low trabecular volumetric density in subjects with polyarticular disease, and both smaller periosteal dimensions and thinner cortices in all JIA subtypes.7
These deficits occurred in association with low muscle mass, consistent with a bone disorder secondary to sarcopenia.37
The authors suggested that effective arthritis treatment and physical activity promotion may be the optimal methods to enhance bone health in JIA.
Coordination and sedentariness also influence fracture susceptibility.38,39,40
In JIA, flexion contractures, muscle weakness, and musculoskeletal pain may contribute to an abnormal gait, poor balance, and increased risk of injury.41,42
Even in the absence of active arthritis, gait may be abnormal and peak impact during jumping may be increased and imbalanced.43
Fusion or abnormal range of motion of the wrist in arthritis may unfavourably alter forces on an outstretched arm during a fall, amplifying the risk of fracture. The extent to which lower physical activity contributes to the risk of fracture in children with arthritis is unknown.44
There are limitations to our study that should be mentioned. Firstly, we chose a broad definition of childhood arthritis to identify our study population. The most common diagnostic codes were “arthritis” and “synovitis,” which potentially reflect a lack of familiarity among primary care providers with the classification of JIA.45
Also, our study group may include children with brief episodes of reactive arthritis. However, the lack of specificity in the diagnostic codes used to identify subjects with arthritis would probably reduce the observed fracture risk. Secondly, adults who communicated a history of arthritis during childhood might not be representative because those with severe or persistent disease may have been more likely to report the diagnosis. This potential for recall bias does not negate the high fracture risk in adults reporting childhood onset arthritis, but the finding may not be generalisable to those with a history of mild or inactive disease. Additionally, these subjects were likely to have received chronic glucocorticoid treatment, placing them at increased risk for fracture.46
We were disappointed by the paucity of detail in the records documenting DMARD use. Possibly, DMARDs were more commonly prescribed by rheumatologists and not entered into the GPRD medication record, although this does not appear to be the case in adults with RA.47
A survey recently revealed that 82% of family practitioners were more confident about managing arthritis in adults than in children.45
The sparse documentation of DMARD use precluded a meaningful analysis of fracture incidence in subjects with arthritis exposed to drugs potentially associated with fracture risk. There was a suggestion that methotrexate use may be protective against fracture, but this effect was not statistically significant.
Three possibilities may explain our the observed lack of association between DMARD use and fractures. Firstly, DMARD and glucocorticoid use may be protective, because improved disease control may protect against poor bone accrual or frank bone loss. Recent studies in adults with RA support this hypothesis.48,49
Haugeberg and colleagues recently reported that hand bone loss in RA was associated with mean C reactive protein and rheumatoid factor status, but not with age, Health Assessment Questionnaire score, or glucocorticoid use.48
In a randomised clinical trial, Haugeberg et al
found that glucocorticoid use was protective against bone loss in the hand.49
In the glucocorticoid treated group, the relation between C reactive protein levels and bone loss was reduced. Secondly, some subjects with a history of severe but inactive disease may be represented in the database. These subjects were likely to remain at high risk for fracture owing to a history of poor bone accrual or low peak bone mass. Thirdly, differential misclassification of DMARD or glucocorticoid treated subjects as non‐treated would potentially bias results toward the null hypothesis if these subjects were, in fact, at higher risk for fracture.
If the documentation of DMARD and glucocorticoid use in our study was accurate, the cohort presented would represent one with mild and inactive disease, presumably at lower risk of osteoporosis than more severely affected subjects with JIA. Alternatively, infrequent DMARD and glucocorticoid use in active disease would probably contribute to poor bone accrual and heightened fracture risk. Each of these two possibilities may affect the generalisability of our study. Additionally, the lack of anthropometric data in the subject records, as has been noted in a prior paediatric GPRD study,50
precluded an analysis of body mass index as a predictor of fracture risk.
Our study sample includes the period between 1987 and 2002. Therefore, adults and the majority of children did not benefit from biological therapies. Recent improvements in disease control associated with the availability of effective drugs may protect against bone loss, augmenting peak bone mass in afflicted children. However, recent studies demonstrate a continued threat to skeletal integrity, even in the era of biological treatment.7,14
In conclusion, childhood arthritis is associated with a substantially increased risk of fracture that is most marked during adolescence and over the age of 45 years. Although studies of bone health in JIA have been limited by suboptimal imaging techniques and analytical challenges, this study demonstrates a significant clinical problem requiring further study. The immediate goal should be to identify children with JIA at high risk for fracture to target for clinical trials.