Osteoporosis is a public health problem worldwide. An important determinant of osteoporosis and future fracture risk is the peak bone mass achieved during the period of skeletal growth. Skeletal maturation in children is dependent on the rate of bone formation exceeding the rate of bone resorption. Peak bone mass is defined as the bone mass present at the end of skeletal maturation, which occurs after age 20 years. If a sound foundation for peak bone mass, which is partly genetically determined, is not established during the second decade of life, the young adult will experience osteopenia and an increased fracture risk (1). Children with a chronic illness such as arthritis are at risk of developing osteopenia that is influenced by (in addition to heredity and hormones) inflammation, medication, nutrition, and physical inactivity.
In several cross-sectional long-term followup studies, reduced bone mineral density (BMD) in adults with juvenile idiopathic arthritis (JIA) has been reported (2–5). Several studies (mainly cross-sectional) have demonstrated reduced BMD or bone mineral content (BMC) in children and adolescents with JIA. These findings were recently summarized in 2 review articles (6, 7).
Pepmueller et al focused on the fact that impairment of bone formation during the critical period of pubertal growth acceleration may not be reparable later in life (8). The extent of low bone mass as a long-term complication in adolescents with onset of JIA as infants or at preschool age is not well documented. In addition, few studies have been published in which disease variables and patient characteristics are related to the development of osteopenia and osteoporosis in these patients.
In order to address these issues, we examined BMD and BMC of the total body, spine, hip, and forearm as measures of long-term outcome in 105 adolescents with early-onset JIA. These adolescents are part of a cohort of patients with JIA, ages 13–31 years, who were first admitted to Rikshospitalet University Hospital between 1980 and 1985 and were followed up for a median of 14.9 years after disease onset.
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- PATIENTS AND METHODS
In this long-term outcome study, 41% of the adolescents with early-onset JIA had low total-body BMC at followup. Low total-body BMD was observed in 34% of the patients, low lumbar spine BMD was observed in 25%, and low femoral neck BMD was observed in 31%. Low BMD was more frequent in adolescents with early-onset JIA than in young adult patients with later-onset JIA. Seventy-one percent of the patients were not being treated with corticosteroids, and 39% of these had low bone mass. Total-body BMC was related to duration of active disease, disease severity, weight, and height. Our results are in accordance with the frequencies of low total-body bone mass in non–corticosteroid-treated postpubertal females reported by Henderson et al (34). Those investigators observed low BMC in 11 (31%) of 36 patients. To our knowledge, there are no other studies in which the frequencies of low bone mass in cohorts of adolescent JIA patients are reported.
The frequencies of low BMD in our cohort were significantly higher among the adolescents with a median age at JIA onset of 2.4 years than in the young adults with a median age at JIA onset of 10.3 years. These results are in accordance with those from another study involving our cohort, showing that young age at onset was a predictor of unfavorable outcome in JRA (10). Our findings corroborate data from a study by Badley and Ansell showing unfavorable outcome, with a higher incidence of fractures, in female JRA patients in whom the disease commenced before age 5 years compared with patients with an older age at disease onset (35).
Among the 216 young adult JIA patients, 33 (15%) were found to have low BMD of the total body, 32 (15%) had low BMD of the spine at L2–L4, 33 (15%) had low BMD of the femoral neck, and 53 patients (25%) had low BMD in one-third of the distal radius. In a population-based study in Rochester, Minnesota, French et al (2) reported results in accordance with ours for BMD of the radius and total body, but they observed higher frequencies of low bone mass in the spine (28%) and femoral neck (32%). Zak et al (3) and Bartram et al (4), in cross-sectional long-term followup studies, reported frequencies of low bone mass in the spine and hip of 40–52%. Different patient populations and differences in disease activity and disease duration may explain the conflicting results of these studies.
In this group of adolescent patients with early-onset JIA, duration of active disease, the number of joints with restricted mobility, height, weight, bone area, and age at followup were found to be the most important variables explaining the variance in total-body BMC by multiple linear regression analyses. Patients with low bone mass had higher ESRs, higher frequencies of joint erosions, and greater disability compared with patients with normal bone mass. These results are in accordance with those of several other studies showing a relationship between bone loss and disease activity and between bone loss and number of involved joints in JIA patients (8, 34, 36–41).
The urinary level of D-Pyd was another important variable that explained the variance of total-body BMC by multiple linear regression analyses. If this finding of a higher urinary concentration of D-Pyd is considered together with our findings of higher serum levels of bone-specific AP, osteocalcin, and C-telopeptide 1 in patients with low total-body BMC compared with patients with normal BMC (although these findings were not statistically significant), it might indicate an increased bone turnover in these patients. Similar results have been reported by Henderson et al, who found significantly higher levels of osteocalcin and C-telopeptide 1 in patients with low total-body BMC (34). In contrast, Pepmueller et al (8) and Hillman et al (42) found decreased levels of bone-specific AP, osteocalcin, and the bone resorption marker tartrate-resistant acid phosphatase in children with active JRA, suggesting reduced bone turnover. The differences between the bone marker findings may be attributable to differences in age, corticosteroid therapy, and disease activity, all of which may complicate the interpretation of the findings.
Four of the 5 adolescent patients who were currently receiving corticosteroids had low bone mass. Previous users of corticosteroids did not have increased frequencies of low bone mass. The cumulative dose of corticosteroids, expressed as months of prednisolone treatment, did not contribute significantly to the variation in total-body BMC as assessed in the multiple regression analyses. Our data are in accordance with the results of a meta-analysis by van Staa et al, who found strong evidence suggesting that corticosteroid-induced osteoporosis is reversible after corticosteroid therapy has been stopped (43). The information about prednisolone dose schedules in our study may have been imprecise, because it was obtained from patient interviews and medical records and not from prospective assessments.
Twenty-one percent of the adolescent JIA patients reported having had 1 or more fractures, compared with 17% of their matched controls, but the difference was not statistically significant. Few studies have reported frequencies of fractures in JIA, but a study by Badley and Ansell revealed that 12% of their JRA patients had sustained at least 1 fracture (35).
The adolescent JIA patients engaged in leisure-time weight-bearing activities significantly less frequently than did the Norwegian controls. Weight-bearing activities were not found to be statistically significant as an explanatory variable for the variance in total-body BMC in the multiple linear regression analyses. However, studies of healthy children (44, 45) have shown that weight-bearing activities may be of importance in the development of bone mass.
Our study investigated the long-term outcome for 105 adolescent patients with early-onset JIA, who belonged to a cohort consisting of all the new patients with JIA who were admitted to our hospital between 1980 and 1985. Patients who are admitted to hospital tend to have more severe disease than those who are recruited from the general population. However, the age, sex, and disease onset type of the patients in the cohort were similar to those of patients in previous epidemiologic studies (46–49), indicating that the cohort and the adolescent participants were representative of patients with diagnosed JIA. Because of the health care system in Norway, which provides regular free checkups for all children, most children who had chronic rheumatic disease during the period 1980–1985 have probably been hospitalized. It has been estimated that during this period our hospital admitted ∼70% of Norwegian children with diagnosed JIA (50).
We found that in adolescents with early-onset JIA who were close to the age of skeletal maturation and expected peak bone mass, bone mass in cortical and trabecular bone was reduced. Low bone mass was related to the duration of active disease and disease severity. The possibility of skeletal catch-up growth will influence the future fracture risk of these young people. We know very little about expected catch-up growth for these patients or what factors affect the phenomenon. Studies of the osteoporotic process during different periods of the life course are needed if we are to gain further insight into the development of low bone mass, and particularly to find out whether it is possible to prevent future fractures.