Low bone density is common in children with JIA, lupus and other rheumatologic diseases [2–5]. 30% of mildly to moderately ill pre-pubertal JIA patients who had never been treated with corticosteroids had low total body BMD . Patients with juvenile SLE have a low bone mass without catch-up growth over time, causing a reduction of peak bone mass with high risk of osteoporosis in early adulthood . Local inflammatory factors, decreased physical activity, nutritional imbalances, and medications have all been implicated in bone loss [22, 23]. In our study, many physicians (46%) reported that they would consider measures to identify or prevent corticosteroid-induced bone loss at any steroid dose. However, the preponderance (80%) of the physicians never or rarely obtained a baseline BMD measurement, by any method, before initiating long-term (>6 months) glucocorticoid treatment.
Vertebral fractures are an under-recognized problem in children with inflammatory disorders and they can be present prior to prolonged glucocorticoid exposure. A recent study reported that the incidence of vertebral fractures in children with rheumatologic diseases in the 12 months following glucocorticoid initiation was 6%, and most children were asymptomatic . Another study on children with rheumatic conditions reported that 7% of children had vertebral fractures within 30 days of initiating glucocorticoids . Studies in adults have shown that patients with glucocorticoid-induced osteoporosis experience fragility fractures at better DXA scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes . Therefore, prevention and early diagnosis of low bone density is important in pediatric rheumatology patients to prevent fragility fractures.
Per the guidelines published by The International Society for Clinical Densitometry in 2013, in the absence of vertebral compression (crush) fractures, the diagnosis of osteoporosis in children is indicated by the presence of both a clinically significant fracture history and BMD Z-score ≤ -2.0. The Society stresses that diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone. However, they recommend that in patients with primary bone disease, or at risk for a secondary bone disease, a DXA should be performed when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture, and the DXA results will influence that management. Per these guidelines, DXA is the preferred method for assessing BMC and areal BMD in children. Despite the data showing the high frequency of asymptomatic fragility fractures in children with rheumatologic diseases who are on long-term glucocorticoids and recommendations by The International Society for Clinical Densitometry summarized above, we found in our study that only 42% of the physicians obtained follow-up BMD measurements annually to screen for low bone density in patients who are on long-term glucocorticoid treatment. Few physicians (only 6%) had a written policy in their department regarding the frequency of BMD measurements in children on long-term glucocorticoid treatment.
In our study, DXA was the most commonly utilized diagnostic tool for diagnosis and follow-up of glucocorticoid-induced osteoporosis. None of the physicians who responded to our survey reported using bone ultrasound to monitor bone health in pediatric rheumatology patients who were on long-term glucocorticoid treatment. However, there is a growing body of evidence regarding the use of bone ultrasound in children to monitor bone density. Quantitative ultrasound (QUS) can be used for radiation-free assessment of bone density and “bone quality” by measurement of the ultrasound wave attenuation by bone (BUA) in children with JIA. Bone speed of sound (SOS) shows a significant correlation with BMD as measured by DXA. Portability, ease of use, lower cost, and absence of radiation make QUS of bone a promising means of evaluating BMD in children [25–31].
As stated earlier, there are no guidelines for prevention or treatment of glucocorticoid-induced osteoporosis in children. In our study, 93% of the physicians reported starting calcium supplements frequently or always as a preventative measure for patients who are on long- term corticosteroid treatment. Vitamin D supplements were given always or frequently by 80% of the respondents. In our study, 62% and 49% of the physicians never or rarely prescribed bisphosphonates for their pre-pubertal and pubertal female patients, respectively, with documented osteoporosis; 60% and 50% of the physicians never or rarely prescribed bisphosphonates for their pre-pubertal and pubertal male patients. A possible reason for its limited use in pediatrics is the concern of long-term side effects related to the persistence of bisphosphonates in bone. However, only bone tissue appears to be affected by bisphosphonates in vivo: the very rapid uptake by bone ensures that the other tissues are exposed for only a short period to these drugs (the half-life of circulating bisphosphonates in humans is 0.5-2 hours), and as far as we know, there is no evidence that bisphosphonates maintain any pharmacologic activity once sequestered in the bone . In a prospective multicenter study, oral alendronate was found to be safe and efficacious for the treatment of osteoporosis in diffuse connective tissue diseases in children . Several other studies to date have shown safety and efficacy of bisphosphonates in children [15, 21, 33, 34]. Most commonly reported adverse effects included acute phase type of reactions and flu-like reactions (fever, muscle aches, bone pain) with IV infusion of bisphosphonates which usually responds to acetaminophen or ibuprofen and did not usually occur with further infusions [35–38]. Self-limited mild abdominal pain, nausea, and vomiting after the first infusion of bisphosphonates have also been reported . Transient decreases in serum calcium and phosphate levels after treatment with intravenous pamidronate have been reported [16, 17, 39–41].
Several studies reported normal growth during treatment with bisphosphonates [15, 36, 37, 42]. Metaphyseal banding (zebra lines) can be seen on the radiographs of children receiving cyclical bisphosphonate therapy . The linear growth was found to be normal in several studies after use of bisphosphonates in children [17, 44–46]. There were no effects of commonly used bisphosphonates on the growth plate and bone ages of children corresponded with their chronological age . Bisphosphonate-associated osteonecrosis of the jaw has been reported in adults, but no cases have been reported in children so far .
There is a hesitance to use bisphosphonates in girls and young women of childbearing age due to concerns for potential unfavorable effects of bisphosphonate treatment on the fetus, mainly in the skeleton. Since bisphosphonates are retained for a long time in the human skeleton, concerns have been raised that even pre-pregnancy administration of bisphosphonates may result in embryo-fetal exposure and alter fetal bone modeling.
A recent study reviewed fifty-one cases of exposure to bisphosphonates before or during pregnancy; none of the pregnancies resulted in skeletal abnormalities or other congenital malformations in the infants .
Considering the high incidence of vertebral fractures in children on chronic glucocorticoid treatment and the data supporting safety and efficacy of bisphosphonates in children in general, it can be argued that the benefits of bisphosphonate therapy may outweigh the potential risks in patients with low bone density and frequent fragility fractures. Therefore, bisphosphonates should be considered as a treatment option for children who are on long-term glucocorticoid treatment and have documented osteopenia/osteoporosis.
Calcitonin is a naturally occurring peptide, which inhibits bone resorption by osteoclasts, and is useful for treatment of osteoporosis, reducing vertebral and hip fractures in adult patients. It is usually well tolerated, and its main side-effects are gastrointestinal. It can be administered by injection, orally or intranasally. Calcitonin has been shown to be safe and effective in treatment of steroid-induced osteoporosis in children with nephrotic syndrome . Another recent study of intranasal calcitonin in 10 children with JIA showed a decrease in bone resorption markers and an increase in BMD . Also, calcitonin can rapidly improve symptoms of vertebral fractures . However, because the evidence is limited on the use of calcitonin in children, pediatric rheumatologists infrequently utilize it. 96% of respondents reported “rarely” or “never” prescribing calcitonin for patients on long-term glucocorticoid therapy, and 92% “rarely” or “never” prescribe this medication even for patients with known osteopenia or osteoporosis. More studies are needed in this area.