Chronic liver disease can be cholestatic or non-cholestatic, and both conditions can lead to osteopenia and osteoporosis through malabsorption of vitamin D and calcium or through an impaired vitamin D 25-hydroxylation. Progressive chronic kidney disease leads to “chronic kidney disease-mineral bone disorder” (CKD-MBD) [10]. Children with CKD-MBD have reduced bone density, slowed bone growth, and bone deformity. A short stature associated with bowed legs is characteristic (renal rickets). CKD-MBD is seen in every patient on dialysis, and it has also been detected in children with kidney disease even before they start dialysis. Transplantation of either the liver or kidney however is not followed by a sufficient gain in BMD, because the use of GC and immunosuppressants does not favor a complete recovery. In addition, residual disease and limb deformities from past dialysis therapy in patients with CKD may persist.

Nutritional deficiency due to malabsorption of calcium, phosphate, or vitamin D can lead to softening and weakening of bones, typical features of nutritional rickets. Hereditary forms of rickets, like chronic liver or kidney diseases, impair synthesis of vitamin D. The main source of 25-(OH)D₃ is dietary vitamin D₂. Ultraviolet light stimulates the production of vitamin D₃ from 7-dehydrocholesterol in the skin. However 25-(OH)D₃ is biologically inactive and is hydroxylated in the kidneys to the 1,25-(OH)₂D₃ hormone. The 1,25-(OH)₂D₃ hormone, calcitriol, stimulates intestinal absorption of calcium and increases serum calcium levels. Receptors for 1,25-(OH)₂D₃ are present on intestinal cells and modulate its action (Fig. 44.1).

These patients show low levels of vitamin D (below 10–15 ng/ml) and an increase in PTH. The main function of PTH is to maintain ionized calcium in the physiological range in the blood. Hypocalcemia stimulates PTH secretion, whereas hypercalcemia suppresses its secretion. PTH regulates calcium homeostasis by acting on the major calcium reservoir of the body, the skeleton. It stimulates osteoclastic activity and thereby bone resorption. It also stimulates the conversion of 25-(OH)D₃ to 1,25-(OH)₂D₃. Vitamin D deficiency is more frequent than expected even in industrialized countries, caused by insufficient sunlight exposure and/or inadequate diets [11].

The treatment of vitamin D deficiency is supplementation with calcium and vitamin D. However rickets need correction while a child is still growing; otherwise short stature and skeletal deformities may be permanent. The correction during the years of bone growth allows the resolution of the clinical features, and skeletal deformities diminish or disappear over the course of time.

A specific endocrine disease, Cushing syndrome (CS), is an important cause of structural and functional derangement of bone metabolism. The incidence of fractures in these patients is high (30–50 %) and they frequently involve the spine. Furthermore osteoporosis is present in about half of these patients. When the diagnosis is delayed, long exposure to high steroid levels causes reduced growth velocity and bone age and also causes pubertal delay in the child. PBM is also significantly compromised, in part secondary to a reduction in number and function of osteoblasts, as documented by the reduced levels of alkaline phosphatase and osteocalcin. As CS is typically associated with bone loss particularly in cancellous bones, it is useful to evaluate BMD at the lumbar spine by DXA.

Glucocorticoid-induced osteoporosis is reversible but the recovery is slow and may take 10 years to be complete, thus exposing these children to a high risk of fractures. For this reason some authors propose the use of alendronate especially in children with a persistent high level of cortisol, only in part controlled by surgical treatment. The results of cortisol level normalization are in fact less effective than alendronate, and the decision to discontinue the treatment should be based on clinical monitoring and DXA measurements [12].

Glucocorticoids are frequently prescribed drugs for patients with pediatric rheumatic diseases, nephrotic syndrome, and hematological diseases. These patients are at risk of vertebral and peripheral fractures and reductions in bone mineral density on follow-up. Annual vertebral fracture incidence is 4–6 % in patients with a recent diagnosis, and the prevalence in patients several years post-diagnosis is 7–28 %. The fractures are often asymptomatic and thoracic in location and usually have mild, anterior wedge morphology. Patients affected by systemic diseases associated with a severe inflammation such as SoJIA, SLE, and JDM have a higher fracture risk. Neither glucocorticoid dose nor BMD are ideal predictors for risk of fractures. The muscle involvement and/or associated disease can contribute to the negative effect on bone strength.

Children and adolescents with these conditions seem to have an increased risk of long-bone fractures, especially in the forearm and wrist. However long-bone fractures are not predictive of vertebral fractures. Bone mass increase is typically suboptimal across the years, although the use of potent steroid-sparing anti-inflammatory agents may reverse the trend induced by GC and disease activity. Vitamin D insufficiency may contribute to the disease and warrants ongoing monitoring. Additional studies are useful to understand bone health risks in these children [13].

A systematic review and meta-analysis of existing literature to identify studies of BMD or fractures in children ≤18 years taking systemic GC therapy was performed. Sixteen studies met eligibility criteria, including ten on BMD (287 children) and six on fracture incidence (37.819 children). Spine BMD was significantly lower in children taking GC therapy, compared to age- and gender-matched healthy subjects. Incident clinical fracture rates were variable from 2 to 33 %. However it is not clear if children receiving GC therapy have lower spine BMD compared to children with milder disease not requiring these drugs. Clinical and morphometric vertebral fractures are common in children, although only one study assessed fracture rates in healthy controls [14]. However vertebral fractures are an under-documented complication of childhood GC-treated diseases. Of note, normal variants mimicking fractures exist in all regions of the spine and can be distinguished in two groups:

Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome after 37 days of GC therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry, and the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. Eight percent of these children manifested a single Genant grade 1 deformity. All deformities were mild anterior wedging. 5 % showed one ABQ sign of fracture (loss of endplate parallelism). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. There was inverse correlation between LS BMD Z-score and glucocorticoid exposure for nephrotic syndrome [16].

GCs interfere with trabecular bone architecture. The primary effects are on osteoblasts and osteocytes. Glucocorticoids impair the replication, differentiation, and function of osteoblasts and induce the apoptosis of mature osteoblasts and osteocytes [17]. Although an inverse relationship exists between steroid exposure and LS BMD soon after glucocorticoid initiation in childhood nephrotic syndrome, there was a low rate of vertebral deformities [16].

Glucocorticoids also favor osteoclastogenesis and, as a consequence, increase bone resorption. The end point of these alterations is a net decrease in BMD and alterations in bone quality [18].

GCs are used for control of inflammation associated with asthma in children. The oral use for longer than 3 months is associated with lower BMD; hence, short-term oral GC schedules and/or inhaled GCs are usually chosen. A dose-dependent decline in bone mineral acquisition and increased risk of osteopenia in boys, but not in girls, were seen when administered a short burst of oral GC treatment. Furthermore inhaled GC treatment was associated with a mild decrease in bone mineral acquisition in boys, but not in girls [19]. However inhaled GC treatment is not associated with an increased risk of fractures in children and adolescents [20]. In view of the fact that many patients on inhaled GCs may receive a supplement of oral GC, BMD may be measured in this population during childhood and adolescence.

Rheumatic diseases in childhood and adolescence can lead to secondary osteoporosis. The primary disease, drugs, especially glucocorticoids, and immobility contribute to the development of a reduced BMD.

Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1-β (IL-1-β), and IL-6, cause inflammation-associated osteoporosis by influencing the differentiation and function of osteoblasts and osteoclasts and uncoupling the bone remodeling cycle, with a consequent negative bone balance [21, 22]. Furthermore cytokines directly stimulate osteoclastogenesis, by acting on cells of the osteoclast lineage, and indirectly, by modulating synthesis in target cells of key molecules such as RANKL. Cytokines, especially IL-1-β and IL-6, can upregulate RANKL on osteoclast precursors and increase their sensitivity to RANKL concentrations [23–25]. However, T and B lymphocytes have a central role in the regulation of bone status, especially T-helper 17 (Th17) [26]. IL-17 secreted by Th17 cells is a strong osteoclast activator [26].

Many studies showed that SLE patients have a higher incidence of decreased BMD [9, 24], with a prevalence of osteopenia and PO of 37.5 % and 20.3 %, respectively [9]. In dermatomyositis, along with other factors, the reduced mobilization also plays a major role [24]. A recent study on children with GC-treated rheumatic disorders reported that 6 % of these children had vertebral fracture in the first 12 months of treatment [27]; however a significant bone loss occurs soon after the initial exposure to GC, especially in children with severe inflammation and systemic involvement such as those with SoJIA or connective tissue diseases. However, the effects of inflammation and GC treatment are tightly linked so that it is difficult to extrapolate their relative roles in inducing bone demineralization. A study reported low bone mass (vertebral fractures) in children diagnosed with rheumatic disease even before they began GC therapy [28].

Decreased BMD is present [24, 29] in particular in polyarticular JIA and SoJIA. These patients show a reduced PBM and an increased risk to develop osteoporosis in adult age. Disease severity, inflammatory mediators, and GC have a definitive pathogenetic role for low BMD and reduced PBM [24, 29].

A recent study shows that JSLE has a higher cortical BMD than healthy subjects and JIA patients have a lower cortical BMD than controls. Both JSLE and JIA have a reduced trabecular BMD. Furthermore, JIA patients show a reduction in muscle area compared to JSLE [30].

An abnormal body composition with reduced muscle mass and increased fat is a pathological feature of children with rheumatic diseases and contributes to abnormal bone metabolism [31].

Methotrexate (MTX) has been found to reduce BMD in children with malignancies treated with high-dose protocols [32]. On the contrary, low-dose MTX use in JIA is not associated with a loss in BMD. In fact, the therapeutic effects on arthritis compensate in vivo the inhibitory effects produced in vitro on osteoblasts [33]. Treatment with growth hormone (GH) has been used in children with JIA with a positive effect on growth and BMD, bone geometry, and body composition [34–37]. GH treatment significantly increases total bone and muscle cross-sectional area (CSA) at final height. In accordance with an anabolic effect of GH, fat mass reached the lower limit of healthy children. At final height, cortical and marrow CSA, relative to total bone CSA, had normalized [38].

The selective and effective anti-inflammatory action of biological drugs is helpful in many areas: systemic and articular clinical outcome and bone health. The positive effects on bone metabolism are secondary to the reduction in inflammation, via the blockade of cytokines (TNF-α, IL-1, IL-6) and T-cell or B-cell function. Anakinra, canakinumab, tocilizumab, infliximab, etanercept, and adalimumab are the most used biologics in pediatric rheumatology. However studies on JIA are few [39].

Two studies on children with JIA treated with anti-TNF-α evaluated bone metabolism and documented a reduction in bone loss. Etanercept contributed to reduce bone demineralization after 1 year of treatment [40]. The second study on 16 patients with polyarticular JIA nonresponders to methotrexate documented a reduction in disease activity, an increase in growth velocity, and an improvement of BMD when etanercept was added to methotrexate [41].

Many genes play an essential role in the pathogenesis of PO and may regulate 75–85 % of the bone mass [8, 24, 42]. The PBM reached in healthy individuals is dependent on genetic determinants [43]. Environmental factors (endocrine, mechanical and nutritional influences, lifestyle, calcium and vitamin D dietary intake, drugs) account for 25 % of variability in PBM, which is physiologically attained by 30 years of age [44].

The greatest loss of the bone and mineral occurs in genetic defects, such as osteogenesis imperfecta (OI) and X-linked hypophosphatemic (XLH) rickets, but enzymatic defects such as hypophosphatasia and homocystinuria, Wilson’s disease, and Menkes’ kinky hair syndrome (disorders of copper transport) can lead to severe bone demineralization as well. Rare causes of PO are idiopathic juvenile osteoporosis (IJO) (24), osteoporosis-pseudoglioma syndrome, and juvenile and early-onset Paget’s disease (Table 44.2) [45].