Body Fat Distribution and Metabolic Changes in a Cohort of Adolescents Living With HIV Switched to an Antiretroviral Regimen Containing Dolutegravir.

Use of antiretrovirals is associated to body fat accumulation. We measured body composition in adolescents living with HIV switched to a dolutegravir-containing regimen. Trunk fat and trunk/body fat ratio markedly increased after 12 months. Total and low density lipoprotein cholesterol decreased after 3 months. Increase in trunk fat may put at risk of future cardiovascular problems, despite improvement in the lipid profile.

Update on bone density measurements and their interpretation in children and adolescents.

Following the increased awareness about the central role of the pediatric age in building bone for life, clinicians face more than ever the necessity of assessing bone health in pediatric subjects at risk for early bone mass derangements or in healthy children, in order to optimize their bone mass accrual and prevent osteoporosis. Although the diagnosis of osteoporosis is not made solely upon bone mineral density measurements during growth, such determination can be very useful in the follow-up of pediatric patients with primary and secondary osteoporosis. The ideal instrument would give information on the mineral content and density of the bone, and on its architecture. It should be able to perform the measurements on the skeletal sites where fractures are more frequent, and it should be minimally invasive, accurate, precise and rapid. Unfortunately, none of the techniques currently utilized fulfills all requirements. In the present review, we focus on the pediatric use of dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), peripheral QCT (pQCT), and magnetic resonance imaging (MRI), highlighting advantages and limits for their use and providing indications for bone densitometry interpretation and of vertebral fractures diagnosis in pediatric subjects.

High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity.

Bone health impairment is a common finding in HIV-infected patients on antiretroviral treatment. High serum parathyroid hormone (PTH) concentration in patients on antiretroviral treatment containing tenofovir disoproxil fumarate (TDF) has been reported. Hyperparathyroidism was not always sustained by a reduction in vitamin D concentration. We thus hypothesized a direct inhibitory effect of TDF on the Calcium-sensing receptor (CaSR), leading to hyperparathyroidism. Human embryonic kidney cells were transfected with CASR wild-type gene or mutated in different sites (N124K, T1051G, C788T, T888M). Cells were grown in standard conditions and the activity of CaSR was assessed after stimulation with CaCl2 with and without TDF (100 nM-1 µM). We evaluated by western blot phospho-p44/42 ERK expression levels as a marker of CaSR activity. In silico structure models were obtained for wild-type and N124K mutant. Molecular docking with TDF was also evaluated. The stimulation by CaCl2 and TDF 100 nM led to a decrease of 55% of CaSR activity (P < 0.001), whereas the stimulation by CaCl2 and TDF 1 µM reduced the activity by 68% (P < 0.001). The decreased CaSR activity was comparable to that observed from known CASR gene inactivating mutations (T1051G, C788T), which inhibit the receptor activity by 56% and 78%, respectively. The TDF inhibits the CaSR activity carrying a gain of function mutation in the intracellular domain (T888M), but it does not influence the activity of the receptor carrying the N124K activating mutation. Our data show that TDF is able to inhibit the activity of CaSR in a dose-dependent manner. Hyperparathyroidism observed in TDF-treated patients may be therefore promoted by the direct effect of the drug on CaSR.

Short-Term Vitamin D3 Supplementation in Children with Neurodisabilities: Comparison of Two Delivery Methods.

BACKGROUND/AIMS: Vitamin D deficiency is common in children with neurodisabilities. Oral vitamin D3 may not be absorbed appropriately due to dysphagia and tube feeding. The aim of this study was to compare efficacy of vitamin D3 buccal spray with that of oral drops. METHODS: Twenty-four children with neurodisabilities (5-17 years) and vitamin D deficiency (25(OH)D ≤20 ng/mL) were randomized to receive vitamin D3 buccal spray 800 IU/daily (n = 12) or oral drops 750 IU/daily (n = 12) for 3 months during winter. RESULTS: Both groups had a significant increase in 25(OH)D (z = 150; p < 0.0001). The differences between baseline and final parathyroid hormone measurements did not reach significance in both groups. Markers of bone formation and resorption did not change significantly in both groups. The satisfaction with the formulation was significantly higher in the patients using spray. CONCLUSION: Vitamin D3 supplementation with buccal spray and oral drops are equally effective in short-term treatment of vitamin D deficiency in children with neurodisabilities. Buccal spray may be more acceptable by the patients.

A 10-year follow-up of bone mineral density in HIV-infected youths receiving tenofovir disoproxil fumarate.

BACKGROUND: The use of tenofovir disoproxil fumarate (TDF) has simplified the antiretroviral regimen for HIV-infected patients and improved their compliance with treatment, but it has been associated with decreased bone mineral density (BMD) in adult patients, and data in pediatric patients are debated. The aim of the current study was to assess the long-term effect of TDF on BMD in young patients. METHODS: BMD was measured at the lumbar spine and in the whole skeleton in 26 HIV-infected youths (13 female and 13 male, aged 5 to 17 years at baseline). BMD was measured yearly for 10 years as part of standard care. BMD changes were compared with those calculated from 202 healthy subjects aged 3 to 24 years. FINDINGS: All patients had good control of the infection during the 10-year study. BMD measurements changed significantly (P <0 ⋅ 0001) in HIV-infected youths. The mean annual BMD increment at the lumbar spine was 0 ⋅ 046 (0 ⋅ 006) g/cm2 and 0 ⋅ 042 (0 ⋅ 006) g/cm2 in males and females, respectively. The differences between the slopes of patients and healthy controls were not significant. The annual BMD increment of the whole skeleton was 0 ⋅ 030 (0 ⋅ 005) g/cm2 in males and 0 ⋅ 019 (0 ⋅ 004) g/cm2 in females. The slopes of BMD changes of patients and healthy controls did not differ significantly. INTERPRETATION: These data indicate that treatment with a TDF-containing antiretroviral regimen does not impair BMD in young patients with HIV-infection. Larger studies are needed to confirm these results.

Autosomal dominant hypocalcemia due to a truncation in the C-tail of the calcium-sensing receptor.

Autosomal Dominant Hypocalcemia (ADH) is an endocrine disorder due to activating mutations of the calcium-sensing receptor (CASR) gene. We report on a young boy who presented low serum calcium with hypercalciuria, hyperphosphatemia and low serum concentration of parathyroid hormone, not accompanied by classic clinical signs of hypocalcemia. Treatment with calcitriol and calcium did not normalize serum calcium and renal calcium excretion. The use of thiazide diuretics slightly reduced calciuria. Despite high calcium excretion, no signs of nephrocalcinosis were detected. The patient had a prolonged Q-T interval at ECG, which did not normalize during treatment. PCR amplification of CASR coding sequence and direct sequencing of PCR products. showed a novel heterozygous deletion of a cytosine (c.2682delC), responsible for a frameshift (p.S895Pfs*44) and a premature stop codon resulting in a truncation of the CaSR's C-tail. Functional studies indicated increased activity of mutant receptor compared to the wild-type.

Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets.

CONTEXT: Hypophosphatemic rickets (HR) is a rare disease that includes a group of hereditary and sporadic conditions characterized by renal phosphate loss associated with normal to low vitamin D serum concentration. The most common form is the X-linked hypophosphatemic rickets, with an incidence of 1:20,000. Several mutations have recently been identified in the PHEX, FGF23, DMP1 and ENPP1 genes in patients with HR. Moreover, in vitro and in vivo studies suggested an involvement of MEPE for defective mineralization in HR. OBJECTIVE: The present case series describes the clinical features and the analysis of genes implicated in HR in a cohort of 26 Italian HR patients. SETTING AND DESIGN: All patients were analyzed for the PHEX and FGF23 genes by direct sequencing. When no mutations were detected, Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed. The negative patients were screened for the DMP1, MEPE and ENPP1 genes by direct sequencing. RESULTS: Twenty-two patients (84%) harbored mutations in the PHEX gene. In particular, we detected 19 different mutations, 15 of which were novel. One patient presented a novel splice variation in the ENPP1 gene while no alterations were identified in the FGF23, DMP1 and MEPE genes. The genetic study of the families showed that 11 patients (55%) had de novo mutations. Clinical presentation and disease severity did not show an evident correlation between the mutation types. CONCLUSIONS: This report represents the first large familial study performed on Italian patients. It confirms that mutations in PHEX are the most frequent cause of HR. Furthermore, the variety of clinical manifestations identified in our HR patients underlines the extreme clinical and genetic heterogeneity of this disease.

Sclerostin and DKK-1: two important regulators of bone metabolism in HIV-infected youths.

Reduced bone mineral density (BMD) and altered bone metabolism are common findings in HIV-infected patients. Increased bone formation has been described both in HIV-infected adults and children. Wnt ligands promote bone formation by stimulating osteoblast differentiation and their survival. Sclerostin and dickkopf factor 1 (DKK-1), Wnt antagonists, are important negative regulators of bone formation. We studied 86 HIV-infected patients whose ages ranged from 5.7 to 27.9 years. Patients were all on antiretroviral therapy, but seven who were naïve to treatment. Bone alkaline phosphatase (BAP), sclerostin, and DKK-1 were measured in serum by enzyme immunoassay. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and in the whole skeleton. Biochemical indexes were also measured in 143 healthy controls (age range 4.5-27.4 years). HIV-infected patients had lower than normal BMD (spine P < 0.005, and whole skeleton P < 0.03). BAP measurements were significantly higher in HIV-infected patients than controls (P ≤ 0.05). Sclerostin and DKK-1 concentrations were markedly lower than in controls (P ≤ 0.0006, and P ≤ 0.03, respectively). The serum concentration of both analytes of patients naïve to antiretroviral treatment was not different from that of treated patients. No correlations were found between sclerostin, DKK-1, and bone mineral measurements. Our data confirm the alteration of bone metabolism pathways in HIV-infected individuals. The lower concentration of Wnt antagonists is consistent with the increased bone formation markers.

Areal bone mineral density in pediatric patients with chronic hepatitis B or chronic hepatitis C.

Decreased bone mineral density (BMD) is a known complication of chronic liver disease in adults. Data on bone mass, an important factor for the development of osteoporosis in adult life, in young patients with chronic hepatitis B (HBV) and C virus (HCV) infections are scarce. We measured BMD at the lumbar spine and whole skeleton by dual-energy X-ray absorptiometry in 11 HBV- and 21 HCV-vertically infected untreated youths (3.9-21.1 years). BMD measurements were compared to those of 202 healthy subjects (3.0-21.9 years). The median BMD Z-score of the lumbar spine of HBV-infected patients was -0.3, ranging from -1.6 to 0.6, while the median whole skeleton BMD Z-score was 0.1 (-0.8 to 0.6). HBV-infected patients showed a median Z-score of the lumbar spine of 0.6 (-1.6 to 1.9), and a median whole skeleton BMD Z-score of 0.6, ranging from -1.5 to 1.4. Multivariate analyses have been performed to correct for differences in sex, age, and anthropometric measurements. Lumbar spine BMD values of HBV and HCV-infected patients were not significantly different from those of controls. Similarly, no differences were found between groups in total body BMD measurements. Our data suggest that, unlikely adult patients, untreated young patients with chronic HBV and HCV infection may not have impaired bone mass measurements.