This study is the first to compare QCT, which allows separate measurements of cortical and trabecular bone mineral density, with bone biopsy, the reference standard for evaluating bone, in a cohort of 15 children with idiopathic juvenile osteoporosis. Major findings include the description of decreased bone turnover in many patients, a decrease in both trabecular and cortical Z-scores for bone mineral density, and a relationship between both cortical and trabecular bone density with parameters of bone histology, thus allowing a non-invasive evaluation of cortical and vertebral bone volume in these children.
Two large clinical cohorts of IJO patients have been previously reported, containing 21 and 61 patients respectively [16, 17]. The median age at first symptoms in the current cohort was similar to these previous studies by Smith et al. , and Lorenc et al. ; however, a greater proportion of males (73%) was present in the current study with a significantly greater number of males presenting with clinically severe osteoporosis. Of note, the majority of patients in the current cohort demonstrated normal or high height percentile for age at referral; this clinical feature may distinguish idiopathic juvenile osteoporosis from other constitutional bone diseases at the time of the first evaluation.
Histomorphometric data from Rauch et al. have described the presence of decreased bone formation, in the absence of increased bone resorption or cortical damage, in trabecular bone of patients with idiopathic juvenile osteoporosis . They thus hypothesized that the condition may be due to the presence of an apparently normal number of osteoblasts whose function is altered, leading to a decreased rate of matrix deposition . In the current study, we have confirmed the findings by Rauch et al. demonstrating decreased bone turnover in the majority of patients; however, a greater variability in mineralization and volume parameters were noted in our cohort. In comparison with Rauch et al., histomorphometric parameters of trabecular bone turnover, mineralization, and volume were higher in the current cohort. These discrepancies may be explained in part by the differences between the reference values.
Published data on bone mineral density in children with idiopathic juvenile osteoporosis have been obtained from DXA. Using this technique, Lorenc et al. reported that total body bone mineral density was lower than the normal for age . Although it has been widely used in children, the areal measurement of bone mineral density by DXA has at least two main limitations in children: its reliance on areal density rather than volumetric density, a parameter which is modified by growth, and its inability to distinguish between trabecular and cortical bone compartments which have different physiology and growth patterns [6, 18]. More recently, Mayranpaa et al. performed DXA and bone biopsy in a cohort of 24 consecutive children (17 males, median age 12 years) presenting with idiopathic osteoporosis. They showed that histomorphometric findings correlated poorly with fracture history, circulating bone biomarkers and DXA findings; in contrast, vitamin D deficiency and low lumbar BMD were associated with high bone turnover on the biopsy . In this series, we also found an association between vitamin D status and bone biopsy results, with a relationship between 25 (OH) vitamin D levels and bone mineralization. We also found a direct link between serum PTH levels and trabecular bone volume that were not described in the Finnish study.
In the current study, which used QCT to discriminate cortical and cancellous bone compartments, a decrease in both trabecular and cortical BMD Z-scores was observed, with greater impairments in trabecular BMD, confirming previous reports which highlighted the greater importance of impaired trabecular bone in patients with idiopathic juvenile osteoporosis. However, the low Z-score for both BMD and cross-sectional area in the cortical compartmentmay explain the important frequency of cortical fractures also observed in this cohort; indeed, even though children with IJO are usually known to present both vertebral compression fractures and long bone fractures, in our series, only two patients presented with vertebral compression fractures whereas long bone fractures and extremity fractures (e.g., toes, metatarse) were much more frequent; however, due to the retrospective design of the study, compression fractures were not systematically screened in the patients, but only in case of clinical symptoms. Furthermore, the association between histomorphometry and QCT parameters highlights the potential interest of this non-invasive three-dimensional imaging technique for the follow-up of children with IJO. In some patients the biopsy and QCT were not obtained at the same age due to the retrospective design of the study and may have lessened the association between QCT and bone biopsy; however, to the best of our knowledge, this association between QCT and bone biopsy has never been evaluated in pediatrics and further prospective studies are warranted to evaluate its potential clinical and therapeutic ramifications. Moreover, after the new definition in 2000 of osteoporosis by the National Institute of Health (NIH), adding ‘quality’ criteria in addition to the quantitative evaluation of BMD, new bone imaging techniques have been developed, including High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT), and therefore leading to an improvement in bone evaluation. Indeed, HR-pQCT can assess both compartmental (i.e., total, cortical and trabecular) volumetric BMD and trabecular microarchitecture . This technique, corresponding to an improvement of QCT, has already been validated in other pediatric populations [20, 21]; it could theorically be of interest in patients with IJO and should be evaluated in the future.
Recent studies have reported an association between mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) and low bone mass in children ; however, these data cannot fully explain the pathophysiology of juvenile osteoporosis, and the initial trigger of the decreased osteoblast performance remains to be determined. In the context of idiopathic juvenile osteoporosis, Laine et al. recently described a higher prevalence of LRP5 polymorphisms in a cohort of 27 children (14 males) . Notably, they also found that one-third of the patients had at least one parent with a BMD below the expected range for age . In our series of case, ten patients underwent fibroblast analysis or direct gene analysis to rule out Osteogenesis Imperfecta but other genes were not studied. We also found a positive familial history of bone disease in more than half of our patients.
Currently, no evidence-based guidelines exist for the management of idiopathic juvenile osteoporosis. Some case reports have described the potential benefit of bisphosphonate therapy [24–26]; however, few controlled studies exist in the use of bisphosphonates in children in general and in those with juvenile osteoporosis in particular and the use of bisphosphonates in this population remains controversial due to inadequate long-term efficacy and safety data. Dietary and life-style modifications, including adequate calcium and vitamin D intake, adequate exercise, and avoidance of obesity, may be adopted in all children, including those with IJO, with very little risk. Indeed, the prevalence of 25 (OH) vitamin D deficiency in the current cohort and the association between 25 (OH) vitamin D levels and parameters of skeletal mineralization suggest that early detection and treatment of vitamin D deficiency and insufficiency may be beneficial in this patient population.