RANKL:Osteoprotegerin ratio and bone mineral density in children with untreated juvenile dermatomyositis

Abstract

Objective. To determine bone mineral density (BMD) in patients at the time of diagnosis of juvenile dermatomyositis (DM), to compare the RANKL: osteoprotegerin (OPG) ratio in patients with juvenile DM with that in healthy control subjects, and to evaluate whether BMD is associated with the RANKL:OPG ratio and the duration of untreated disease.Methods. Thirty-seven children with juvenile DM were enrolled. Dual x-ray absorptiometry (DXA) was performed before treatment, and Z scores for the lumbar spine (L1-L4) were determined. The duration of untreated disease was defined as the period of time from the onset of rash or weakness to the time at which DXA was performed. Serum specimens obtained at the time of DXA were analyzed for concentrations of RANKL and OPG, using enzyme-linked immunosorbent assay. The RANKL:OPG ratio was also determined in 44 age-matched healthy control subjects.Results. At the time of diagnosis of juvenile DM, patients had a significantly increased RANKL: OPG ratio compared with that in healthy children (mean ؎ SD 2.19 ؎ 3.03 and 0.13 ؎ 0.17, respectively; P < 0.0001). In patients with a lumbar spine BMD Z score of ؊1.5 or lower, the RANKL:OPG ratio was significantly higher than that in patients with a lumbar spine BMD Z score higher than ؊1.5 (P ‫؍‬ 0.038). Lumbar spine BMD Z scores (mean ؎ SD ؊0.13 ؎ 1.19 [range ؊2.10 to 2.85]) were inversely associated with the duration of untreated disease (R ‫؍‬ ؊0.50, P ‫؍‬ 0.003).Conclusion. Children with juvenile DM have an elevated RANKL:OPG ratio at the time of diagnosis, resulting in expansion of the number of osteoclasts and activation of the bone resorptive function. This may lead to a lack of normal bone mineral accretion and a subsequent reduction in the lumbar spine BMD Z score. Patients with a longer duration of untreated juvenile DM have reduced lumbar spine BMD Z scores. These data suggest that early diagnosis could reduce the likelihood of reduced lumbar spine BMD in these patients by prompting intervention strategies at an early stage.Children with rheumatic disease have decreased bone mineral density (BMD). Studies of BMD have primarily evaluated patients with juvenile idiopathic arthritis (JIA), and an inverse correlation between higher disease activity and lower BMD has been demonstrated in children with arthritis (1-4). Not surprisingly, patients exposed to corticosteroids were observed to have lower bone density (3,4), although bone density also remained low in the absence of corticosteroid exposure (2,5). Recently, a prospective study evaluating children with JIA compared with healthy control subjects demonstrated that not only did children with JIA have decreased bone mineral content at baseline, but that over time the patients had a less-than-expected age-appropriate gain in bone mass (6).Limited data exist concerning bone metabolism in children with juvenile dermatomyositis (DM), which is the most common pediatric inflammatory myopathy, with an annual incidence in the US of 3.2 cases per 1 Dr.

Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

“…In contrast, osteoprotegerin (OPG), another receptor for TRAIL, inhibits TRAIL-induced apoptosis, due to the absence of a death domain [23]. In related studies, we found that sera from untreated patients with JDM contained a significantly lower level of OPG and patients with longer disease duration had an even lower serum OPG level [24], which may be associated with reduced inhibition of TRAIL-mediated apoptosis. However, the role of OPG in JDM requires further investigation.…”

Association of osteoprotegerin and rankl levels with insulin resistance in pubertal obese children

“…Even puberty does not seem to affect OPG concentrations, however the relatively small number of children that participated in our study make it difficult to draw a conclusion in this regard [16]. Controversial data exist in the literature regarding the association between OPG/RANKL system and BMD [6,7,[9][10][11][12]. Bucay N et al demonstrated a lower BMD and a higher incidence of fracture among OPGdeficient mice [8].…”

“…In this process, a RANKL-ligand present on the osteoblasts binds to RANK on osteoclast precursors to provoke their differentiation and inhibit osteoclast apoptosis [5,6]. Although OPG's mechanism of action has been described by in vitro and animal studies; human studies on OPG that investigated its association with BMD and other variables have yielded variable results and mostly failed to demonstrate a correlation between OPG and BMD [6][7][8][9][10][11][12]. Additionally, several studies on adults have suggested that OPG may have some effect on angiogenesis other than its association with vascular injury and atherosclerosis [12,13].…”

Prevalent vertebral fractures among children initiating glucocorticoid therapy for the treatment of rheumatic disorders

“…Our study stands unique for its timing of patient evaluation within 30 days of glucocorticoid initiation. The only other study conducted early in the course of the illness was by Rouster-Stevens et al (18), who assessed spine areal BMD by DXA in 37 children with untreated juvenile DM. They found that 6 (18%) of 33 evaluable patients had L-spine areal BMD Z scores less than Ϫ1.5, and that the L-spine BMD Z score was related to disease duration.…”

“…Reductions in lumbar spine (L-spine), femoral neck, and distal radial bone mineral density (BMD) in children with juvenile idiopathic arthritis (JIA) have been consistently documented among those who have been treated with glucocorticoids (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and those who have not (1-6,8,9,12,14 -16). Reduced Lspine BMD has also been shown in children with juvenile dermatomyositis (DM) (17)(18)(19)(20)(21) and in juvenile systemic lupus erythematosus (SLE) (3,(21)(22)(23)(24)(25)(26)(27).…”