The foundations for bone fragility in old age are probably partly established during growth, and disorders affecting bone growth, such as childhood illness, have been proposed as an important contributing factor (1). Bone growth and underlying cell biology are complex, little understood processes (2). In active juvenile arthritis, bone mineral accrual may be reduced around affected joints and in skeletal sites distant from the diseased joint. Bone morbidity is influenced by inflammation, medication, nutrition, and physical inactivity (3). Although there are several studies demonstrating reduced bone mass in patients with juvenile idiopathic arthritis (JIA) (4, 5), there are few prospective data on bone mass and bone turnover from an early disease stage in these children.
This study explores early changes in, and predictors of, bone mass in children with JIA in order to identify patients who are likely to develop reduced bone mass. A patient cohort and a matched cohort of healthy children were followed up prospectively. Changes in total body, spine, femur, and forearm bone mineral density (BMD) and bone mineral content (BMC), as well as body composition and fracture rates were examined.
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- MATERIALS AND METHODS
In this 2-year prospective longitudinal study of early JIA patients and healthy children, we found lower gains in total body BMC, distal radius BMC, and total body lean mass and higher gains in total body fat in the patients compared with the healthy children. Low or very low total body BMC was observed in 24% of the patients and in 12% of the controls at followup, and the patients had lower levels of markers of bone formation and bone resorption. Predictors of the changes in total body BMC were the JIA, bone markers, and weight-bearing physical activity. Patients with a low total body BMC at followup seemed to have more active disease at baseline.
Our patient cohort was taken from a referral-based center for children with pediatric rheumatic diseases. We serve ∼70% of the Norwegian population of 4.5 million inhabitants. Although our patient group is referral-based, it is comparable to the JIA patients in epidemiologic studies with regard to age, sex, and distribution of disease-onset type (27, 28).
Our study has several strengths. Ninety-six percent of all subjects who were enrolled completed the study. The healthy children were randomly chosen from the population and individually matched with the patients according to age, sex, ethnicity, and geography. The geographic match may reduce a bias caused by geographic differences in femoral neck geometry, BMD, and fracture rates related to environmental factors or genetic risk determinants (29, 30).
Published data on bone mass development during the first years of JIA is sparse. To our knowledge, this is the first prospective controlled cohort study of bone mass gains and bone turnover in children early in the disease course.
Markers of bone formation (serum bone-specific alkaline phosphatase) and bone resorption (serum C-telopeptide of type I collagen) were predictors of the changes in total body BMC in the controls as well as in the patients by multiple regression analysis. Bone formation markers had lower values in the patients than in the controls both at baseline and at followup, whereas bone resorption was greater in the patients at baseline and less pronounced at followup. These observations indicate that there is a reduction in bone turnover early in the disease course. The results are consistent with the results from studies of bone turnover in patients with a longer disease duration (31–33). Although corticosteroids are known to reduce bone turnover in children (18), the proportion of our patients who were currently receiving oral corticosteroids fell from 19% at baseline to 12% at followup, and cannot be the only explanation for the reduction in bone turnover during the observation period.
Body composition was altered in the patients; lean mass decreased and fat mass increased. A higher percentage of body fat in patients than in healthy children has previously been reported (32). The altered body composition is probably related to chronic inflammation and reduced physical activity.
Reduced physical activity means that the muscle force applied to bone is diminished, which in turn, may result in low bone mass (34). Studies of healthy children indicate that the growing skeleton is sensitive to, and benefits from, exercise (35–37). Weight-bearing physical activity was a predictor of the increase in total body BMC both in the healthy children and in the patients, although the patients engaged in weight-bearing activities less frequently than the controls. Few studies have analyzed the effects of physical loading in JIA, but weight-bearing physical activity was found to be a positive determinant of bone mineral volumetric density of the femoral neck in a Finnish patient group (38).
The presence of JIA was a predictor of lower gains in total body BMC, but the disease activity variables were not found to be significant in the regression analysis. However, we did find an association between disease activity and low bone mass, which has also been found in several other studies of childhood arthritis (4, 5). It is not known what dosage and duration of oral corticosteroids is needed for the development of osteoporosis in children. Our results showed an association between current corticosteroid use and decreased bone mass Z scores, but the cumulative corticosteroid dose and previous use of corticosteroids were not significant predictors of reductions in bone mass gains. These results are consistent with our findings in a long-term outcome study of adolescent patients with JIA (13). The findings are also consistent with a recent published study of children with nephrotic syndrome who were treated with an average cumulative dose of 23,000 mg of glucocorticoids and without the expected deficits in bone mineral content of the spine or total body (39). Those authors proposed that the finding may reflect the ability of the growing skeleton to sustain glucocorticoid-induced reductions in bone formation and to recover during intervals of remission.
Activated vitamin D is a key regulator of calcium phosphate metabolism, which is important for optimal growth and mineralization. During the winter, limited exposure to sunlight reduces the synthesis of vitamin D in the skin in populations living in countries at high latitudes such as ours, and dietary intake of vitamin D becomes more important. The low dietary intake of vitamin D and the low serum levels of 25-hydroxyvitamin D found in our study subjects may be of clinical importance. Low serum levels of 25-hydroxyvitamin D in healthy children have also been found in other studies of Scandinavian populations (26).
While the identification of pediatric osteoporosis has progressed in the last 10 years, there is still a need for longitudinal studies to investigate the natural history of the various forms of childhood osteoporosis (40). The present prospective study indicates that a process leading to diminished bone mass starts early in the disease course of JIA. The decreased gains in bone mass were both generalized and localized around affected joints, and affected both trabecular and cortical bone. However, the observed reductions in bone mass were moderate. Our knowledge of bone catch-up growth is sparse. To fully define the natural history of osteoporosis in JIA, pediatric cohorts should be followed up with longitudinal studies over a longer period.