Although there have been several studies characterizing the effect of SLE on skeletal parameters in children and young adults, this is the first report to specifically examine the relationship between SLE disease activity and bone turnover in this population. Such a distinction is important because the effects of SLE treatment and SLE disease activity itself on the developing skeleton may be distinct. For example, while we found evidence of decreased bone formation as a result of SLE treatment (as measured by glucocorticoid dose), we also found an independent association between SLE disease activity and reduced bone resorption in this population. Although it may initially seem counterintuitive to observe serum biomarker evidence of reduced bone resorption among individuals with more active SLE, especially in light of multiple reports indicating decreased BMD in this population [11
], such a result may explain why patients with SLE have less bone loss than expected compared with other rheumatic diseases such as RA [33
]. For example, in a comparison of young adults with SLE on high-dose steroids with those with RA on low-dose steroids, patients with SLE had higher bone mass than did RA patients, despite the higher steroid doses in these SLE patients [33
]. In keeping with this observation, subjects in our cohort had decreased BMD, though in most cases this was not severe. It is notable that, in contrast to RA, the arthritis of SLE does not produce bony erosions, perhaps reflective of a greater propensity for bone preservation in SLE than in RA. As our study shows that the predominant effect of SLE disease activity on bone metabolism is a decrease in bone resorption, we propose that the low BMD seen in SLE may result primarily from disease treatment (e.g. with CSs) rather than from the underlying disease itself. This idea is supported by reports showing that CS dose is a greater contributor than disease duration to low BMD in childhood SLE [15
] as well as in adult SLE [34
]. In addition, our data demonstrate a robust negative association between CS dose and serum osteocalcin, suggesting that CSs have a powerful inhibitory effect on bone formation.
A significant association between bone turnover markers and BMD was not found in this study, likely reflecting the fact that BMD is a long-term measure of overall bone mineralization, whereas serum bone turnover markers in children are more dynamic measures. Supporting this idea are studies showing a variable association between baseline levels of bone turnover markers and longitudinal changes in BMD in children [36
The mechanism by which SLE disease activity leads to decreased bone resorption is currently not known. Our data suggest a role for the Type I IFNs, specifically IFN-β, in the effect of SLE on bone turnover in children. The Type I IFNs are elevated in active SLE, leading to altered gene expression in peripheral mononuclear cells [16–18
]. Children receiving exogenous Type I IFNs for treatment of hepatitis B have increased BMD, pointing to a bone-protective effect of these cytokines [38
]. Of the Type I IFNs, IFN-β has a particularly important function in regulating bone metabolism. Mice deficient in IFN-β have severe osteopenia resulting from enhanced osteoclastogenesis, resulting from IFN-β’s direct inhibition of osteoclastogenesis via inhibition of c-fos [20
]. The potential therapeutic benefit of IFN-β has been demonstrated in an animal model of endotoxin-induced inflammatory arthritis, where daily administration of IFN-β inhibited bone resorption [21
]. A recent study in humans demonstrated that IFN-β is 100-fold more potent than IFN-α in inhibiting osteoclast development [19
]. Our studies did not find a significant association between IFN-α and bone turnover markers in SLE. This may be due to the rapid breakdown of IFN-α in serum, which has made measurement of this molecule in serum samples problematic [39
]. Whether IFN-β or other Type I IFNs are essential mediators of decreased bone resorption in childhood SLE remains speculative and should be further explored in future studies.
While our study uniquely examines bone remodelling in a moderately sized and ethnically diverse cohort of children and young adults, several limitations must be considered. First, our study was restricted to the outpatient population, leading to a bias towards less active SLE. Secondly, as our bone turnover and cytokine samples were collected at outpatient clinic visits, we did not control for diurnal variation. Thirdly, the use of bone turnover markers in children is always complicated by growth-related changes in bone formation and resorption [40
]. For this reason, we included age in our multivariate models. Lastly, our measurements of TRAP were not specific to the 5b isoform of this enzyme, which is viewed to be more specific to osteoclasts [42
]. Thus, measured TRAP levels in our study may reflect the production of this enzyme by other cells of the myeloid lineage such as macrophages and dendritic cells in addition to that produced by osteoclasts [43
]. Despite this limitation, it is reassuring that our observations for TRAP were consistent when applied to urine NTx.
In summary, our study demonstrates an association between increased SLE disease activity and reduced bone resorption in children and young adults. Our results suggest that enhanced bone resorption due to SLE activity itself is not the primary factor driving bone loss in childhood-onset SLE; rather, another factor, such as treatment effects, likely drives this process. If so, minimizing CS exposure may be more important than prevention of disease flares in protecting the skeleton from adverse effects of childhood-onset SLE. Our findings also suggest that bone loss in SLE may differ from that seen in RA and other rheumatic diseases, pointing to the need for a disease-specific approach when examining the nature of bone loss among the rheumatic diseases. Improved understanding of the pathways involved in bone metabolism in childhood-onset inflammatory diseases will ultimately inform the development of improved prevention and treatment strategies for the adverse skeletal outcomes in SLE and related illnesses.