Osteoporosis in children and adolescents:when to suspect and how to diagnose it

Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis. Conclusions: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children.What is Known:• Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life.• The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary.What is New:• Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis.• We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis

Growth and Body Composition in PKU Children-A Three-Year Prospective Study Comparing the Effects of L-Amino Acid to Glycomacropeptide Protein Substitutes

Protein quality and quantity are important factors in determining lean body (muscle) mass (LBM). In phenylketonuria (PKU), protein substitutes provide most of the nitrogen, either as amino acids (AA) or glycomacropeptide with supplementary amino acids (CGMP-AA). Body composition and growth are important indicators of long-term health. In a 3-year prospective study comparing the impact of AA and CGMP-AA on body composition and growth in PKU, 48 children were recruited. N = 19 (median age 11.1 years, range 5-15 years) took AA only, n = 16 (median age 7.3 years, range 5-15 years) took a combination of CGMP-AA and AA, (CGMP50) and 13 children (median age 9.2 years, range 5-16 years) took CGMP-AA only (CGMP100). A dual energy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured LBM, % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups for LBM, %BF, FM and height. The change in height z scores, (AA 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and % BF but this was not statistically significant. There appeared to be no advantage of CGMP-AA compared to AA on body composition after 3-years of follow-up. Although statistically significant differences were not reached, a trend towards improved body composition was observed with CGMP-AA when it provided the entire protein substitute requirement

Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta

Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes

Iron supplementation associated with loss of phenotype in autosomal dominant hypophosphatemic rickets

Context: Autosomal dominant hypophosphatemic rickets (ADHR) is the only hereditary disorder of renal phosphate wasting in which patients may regain the ability to conserve phosphate. Low iron status plays a role in the pathophysiology of ADHR. Objective: This study reports of a girl with ADHR, iron deficiency, and a paternal history of hypophosphatemic rickets that resolved without treatment. The girl's biochemical phenotype resolved with iron supplementation. Subjects: A 26-month-old girl presented with typical features of hypophosphatemic rickets, short stature (79 cm; −2.82 SDS), and iron deficiency. Treatment with elemental phosphorus and calcitriol improved her biochemical profile and resolved the rickets. The girl's father had presented with rickets at age 11 months but never received medication. His final height was reduced (154.3 cm; −3.51 SDS), he had undergone corrective leg surgery and had an adult normal phosphate, fibroblast growth factor 23, and iron status. Father and daughter were found to have a heterozygous mutation in exon 3 of the FGF23 gene (c.536G&amp;gt;A, p.Arg179Gln), confirming ADHR. Intervention: Withdrawal of rickets medication was attempted off and on iron supplementation. Results: Withdrawal of rickets medication in the girl was unsuccessful in the presence of low-normal serum iron levels at age 5.6 years but was later successful in the presence of high-normal serum iron levels following high-dose iron supplementation. Conclusions: We report an association between iron supplementation and a complete loss of biochemical ADHR phenotype, allowing withdrawal of rickets medication. Experience from this case suggests that reduction and withdrawal of rickets medication should be attempted only after iron status has been optimized. </jats:sec

Does maternal deprivation have a bearing on the newborn vitamin D status?

Objectives: Examine the effect of maternal Index of Multiple Deprivation (IMD) on newborn 25-hydroxyvitaminD (25OHD) levels in a multi-ethnic newborn cohort. Design: 3000 dried blood spots (DBS) were gathered from newborns at a regional newborn screening laboratory over two 1-week periods [February 2019 (winter) and August 2019 (summer)]. Data on birth weight, gestational age, maternal age, ethnicity, and post code were collected. Post code was replaced with lower layer super output area (LSOA). IMD quintiles for the corresponding LSOA was used to ascertain socio-economic status (SES) [quintile one (Q1) representing the most deprived 20% and quintile five (Q5) the least deprived 20% of the population]. Each of the seven domains of IMD were examined (income, employment, education, health, barriers to housing and services, crime and living environment). 25OHD was measured on 6mm sub-punch from DBS using quantitative liquid chromatography tandem mass spectrometry and equivalent plasma values derived. Results: A total of 2999 (1500 summer-born, 1499 winter-born) newborn DBS (1580 males) were analysed. 35.7% were vitamin D deficient [25OHD<30 nmol/l] and 33.7% insufficient [25OHD 30-50 nmol/l]. Summer-born newborns had significantly higher 25OHD concentrations compared to winter-born [49.2 vs 29.1 nmol/l respectively, P<0.001]. 25OHD levels varied significantly between the IMD quintiles in the whole (P<0.001) and summer-born cohort (P<0.001), but not in the winter-born cohort (P=0.26), whereby the most deprived cohort had the lowest 25OHD concentrations. Among the seven independent domains of deprivation, living environment had a significant influence on 25OHD levels (β=0.07, P=0.002). In this subdomain, mean 25OHD levels varied significantly between quintiles in the whole (P<0.001) and in the summer-born cohort (Q1 46.45 nmol/l, Q5 54.54 nmol/l; P<0.001) but not in the winter-born cohort (mean Q1 31.57 nmol/l, Q5 31.72 nmol/l; P=0.16). In a regression model, living environment was still significant (P=0.018) and season of birth and ethnicity had a greater effect on 25OHD levels. Conclusion: Maternal living environment has the greatest influence on newborn 25OHD levels among the seven domains of deprivation. Enhanced supplementation and food fortification have been shown to overcome the above non-modifiable risk factors and should be seriously considered

Cumulative radiation exposure from medical imaging and associated lifetime cancer risk in children with osteogenesis imperfecta.

OBJECTIVES To estimate the cumulative effective dose of radiation (E) and additional lifetime attributable risk (LAR) of cancer from ionizing radiation in children with osteogenesis imperfecta (OI), who require frequent imaging for fractures and bone densitometry (DXA) surveillance. Also, to evaluate the pattern of long bone fractures. METHODS We reviewed all imaging (x-rays, DXA and computed tomography [CT]) conducted in a cohort of children with OI with a minimum observation period of 5 years. For each image, E was estimated using age-dependent local data, and LAR of cancer was extrapolated. LAR and fracture data were compared among children with mild, moderate and severe OI. LAR was allocated to cancer risk categories, and the moderate risk group (1 in 1000 to 1 in 100) was evaluated further. RESULTS Results from 106 children with OI (50% females, 5747 images) are presented, with a median (range) observation period of 11.7 (5.2-15.6) years. CT accounted for 0.8% of total imaging procedures but contributed to 66% of total E. The overall LAR of cancer was minimal, averaging an additional 8.8 cases per 100,000 exposed patients (0.8-403). LAR was significantly lower in children with mild OI compared to those with moderate (p = 0.006) and severe OI (p = 0.001). All patients with a moderate LAR of cancer (n = 8) had undergone CT scans and 88% had scoliosis or vertebral fractures. The cohort experienced 412 long bone fractures, with the most common site being the femur (26.5%). OI severity correlated positively with long bone fracture rates (p < 0.001). CONCLUSIONS When compared to baseline LAR of cancer (50%) the additional cancer risk from ionizing radiation imaging in our paediatric OI cohort was small (0.0088%). To reduce additional cancer risk, we recommend replacing spinal x-rays with vertebral fracture assessments on DXA and exercising caution with CT imaging