Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Different Efficacy of Burosumab on Physical Performance and Serum Phosphate in Adult Patients with X-Linked Hyphophosphatemic Rickets during the First Six-Month of Treatment.

Burosumab is a monoclonal anti-FGF23 antibody used to treat patients with X-linked hypophosphatemic rickets (XLH). Its effect on serum phosphate and physical performance was compared in patients during a 6-month treatment with burosumab. Eight adult patients with XHL were treated with burosumab (1 mg/kg s.c. every 28 days). In the first 6 months of treatment, calcium-phosphate metabolism variables were measured, and muscle performance (tested with chair and walking test) and quality of life (tested with fatigue, BPI-pain and BPI-life questionnaires) were estimated. A significant increase in serum phosphate was observed during the treatment. From the 16th week, serum phosphate became significantly lower than its value in the 4th week. No patients had serum phosphate below the normal range at the 10th week, but seven patients were hypophosphatemic in the 20th and 24th week. All patients improved the execution time of the chair test and walking test, which reached a plateau after the 12th week. BPI-pain and BPI-life scores significantly decreased from baseline to the 24th week. In conclusion, a six-month burosumab treatment may significantly improve the general condition and physical performance of adult patients with XLH; this improvement was more stable and more indicative of treatment efficacy than that of serum phosphate.

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management.

X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.

Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > -1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.

Predictive Fat Mass Equations for Children With Inflammatory Bowel Disease.

OBJECTIVE: Evaluate accuracy of skinfold thicknesses and body mass index (BMI) for the prediction of fat mass percentage (FM%) in paediatric inflammatory bowel disease (IBD) and to develop population-specific formulae based on anthropometry for estimation of FM%. METHODS: IBD children (n = 30) and healthy controls (HCs, n = 144) underwent anthropometric evaluation and dual-energy X-ray absorptiometry (DEXA) scan, as the clinical reference for measurement of body composition. Body FM% estimated with skinfolds thickness was compared with FM% measured with DEXA. By means of 4 prediction models, population specific formulae for estimation of FM% were developed. RESULTS: No significant difference in terms of FM% measured by DEXA was found between IBD population and HCs (FM% 29.6% vs 32.2%, P = 0.108). Triceps skinfold thickness (TSF, Model 2) was better than BMI (Model 1) at predicting FM% (82% vs 68% of variance). The sum of 2 skinfolds (biceps + triceps; SF2, Model 3) showed an improvement in the prediction of FM% as compared with TSF, Model 2 (86% vs 82% of variance). The sum of 4 skinfolds (biceps + triceps + suprailiac + subscapular; Model 4) showed further improvement in the prediction of FM% as compared with SF2 (88% vs 86% of variance). CONCLUSIONS: The sum of 4 skinfolds is the most accurate in predicting FM% in paediatric IBD. The sum of 2 skinfolds is less accurate but more feasible and less prone to error. The newly developed population-specific formulae could be a valid tool for estimation of body composition in IBD population and an alternative to DEXA measurement.

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.

Increased fracture rate in children and adolescents with Marfan syndrome.

Marfan syndrome (MFS) is an autosomal genetic disorder of connective tissue, due to alterated fibrillin-1. The aim of our study was to verify the rate of fractures in children with MFS in correlation to bone mineral density and compare the prevalence to the general population in the same latitude. We enrolled 80 patients (37 girls and 43 boys) with the diagnosis of Marfan syndrome, median age 10 y (3 to 17 years). Fracture occurrence was inferred from medical records of patients with MFS. Bone mineral density (BMD) was measured at lumbar spine, femoral neck and total femur by dual-energy x-ray absorptiometry. BMD values were expressed as z-scores, and adjusted for height using height-for-age z-scores. Bone turnover markers and vitamin D were measured. We assessed incidence of fracture in general pediatric population of our geographic area (45°N latitude). A total of 24 fractures were recorded in 21 patients (15 boys and 6 girls), involving both short and long bones, due to mild or moderate trauma. An incidence estimate has been calculated for each year, and an average incidence of 29.2/1000 MFS patients was obtained, markedly higher (P=0.034) than the incidence of fracture calculated in the same geographical area in pediatric patients (15.8/1000). We did not detect differences in anthropometric measurements, BMD values and biochemical indices between patients who fractured and patients who did not. Similarly, no differences were found between patients on losartan therapy and patients not in treatment for the same variables. In conclusion, the incidence of fractures was higher in patients with MFS compared to general population of the same age and latitude. The management of MFS must account bone status health and start strategies of fracture prevention.

Growth hormone therapy in children: predictive factors and short-term and long-term response criteria.

PURPOSE: The definition of growth response in growth hormone (GH)-treated children is controversial. This study aims at: (1) evaluating short-term and long-term efficacy of GH treatment in a cohort of short children with GH deficiency (GHD); (2) assessing and compare various poor response criteria; (3) identifying predictive factors of growth response. METHODS: Our study included 94 children, affected by isolated GHD and treated with GH until they reached final height. Criteria used for calculating the proportion of poor responders to GH for the first year were gain in height (ΔHt) SDS < 0.5 ("Bang criterion"), <0.3 or <0.4 SDS for less-severe and severe GHD, respectively ("Ranke criterion"), height velocity (HV) < mean -1 SDS ("Bakker criterion"); for adult height "Cianfarani criterion" was total ΔHt < 1 SDS. RESULTS: After 1 year of treatment we defined "poor responders" 55.3% of patients according to Bang criterion, 40.9% according to Bakker criterion and 23.4% according to Ranke criterion. At the end of the treatment, poor responders according to Cianfarani criterion were 22.34%; almost everyone in our population (97.9%) achieved mMid-parental height (MPH). Median final Ht was -1.11 SDS. Our analysis revealed a significant negative association between ΔHt and age at diagnosis. CONCLUSIONS: Bang criterion generated the highest number of poor responders, but had a low negative predictive value (67.5%); Ranke and Cianfarani criteria displayed similar rate of poor response. There is no reliable predictive factor of growth hormone response. However, almost all children treated reached MPH, suggesting good treatment efficacy.

Validation of an Accurate and Noninvasive Tool to Exclude Female Precocious Puberty: Pelvic Ultrasound With Uterine Artery Pulsatility Index.

OBJECTIVE. The purpose of this study is to validate the accuracy of pelvic ultrasound (US) with the evaluation of uterine artery pulsatility index (PI) to exclude female precocious puberty. MATERIALS AND METHODS. Tanner breast development score, luteinizing hormone (LH) peak after gonadotropin-releasing hormone (GnRH) stimulation, and uterine and ovarian volumes and diameters were assessed with pelvic US in 495 girls at a single institution. The study population was divided as follows: prepubertal (n = 207), pubertal with physiologic activation of the hypothalamic-pituitary-ovarian axis (n = 176), and central precocious puberty (CPP; n = 112). PI was measured with spectral Doppler US at the ascending branches of the right uterine artery (50-Hz filter; time gain compensation, 73; pulse repetition frequency, 6.6). ROC analyses and t tests were performed. RESULTS. The mean (± SD) PI values in the prepubertal, pubertal, and CPP groups were 6.3 ± 1.4, 3.4 ± 1.1, and 4.1 ± 1.5, respectively (p < 0.001). The best PI cutoff value to distinguish pubertal from prepubertal girls was 4.6 (sensitivity, 83%; specificity, 94%; positive predictive value, 95%; negative predictive value, 80%; accuracy, 87%). ROC AUC values for LH peak (cutoff value, 5 mU/mL) and for spectral Doppler US PI plus longitudinal uterine diameter (i.e., the combination of a PI of 4.6 with a longitudinal uterine diameter of 35 mm) were 0.9272 and 0.9439, respectively (p = 0.7925). The negative predictive values for LH peak and for PI plus longitudinal uterine diameter were 89% and 88%, respectively. CONCLUSION. A PI greater than 4.6 at spectral Doppler US combined with a longitudinal uterine diameter less than 35 mm allows noninvasive exclusion of female precocious puberty with comparable accuracy and lower costs compared to examination of LH peak after GnRH stimulation. Therefore, PI plus longitudinal uterine diameter might be used as a noninvasive first-line test to exclude precocious puberty and thereby avoid further investigations.

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.

Sexual Dimorphism and the Origins of Human Spinal Health.

Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies is on average 10% smaller in healthy newborn girls than in newborn boys, a striking difference that increases during infancy and puberty and is greatest by the time of sexual and skeletal maturity. The smaller CSA of female vertebrae is associated with greater spinal flexibility and could represent the human adaptation to fetal load in bipedal posture. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities. This review summarizes the potential endocrine, genetic, and environmental determinants of vertebral cross-sectional growth and current knowledge of the association between the small female vertebrae and greater risk for a broad array of spinal conditions across the lifespan.

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.

Mild TSH resistance: Clinical and hormonal features in childhood and adulthood.

OBJECTIVE: Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. DESIGN: Observational, retrospective study. PATIENTS: Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. MEASUREMENTS: The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15 years). RESULTS: Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. CONCLUSIONS: Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.

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.

A biochemical approach for assessing cutoffs at the age thresholds of 14 and 18 years: a pilot study on the applicability of bone specific alkaline phosphatase on an Italian sample.

BACKGROUND: The majority of age estimation methods analyze morphological changes of specific skeletal (or dental) structures reflecting global bone development (biological parameter) in order to estimate a chronological value. This morphological and structural development is the consequence of a very active tissue metabolism and intensive modeling process which involve both bone formation and bone resorption. Several biochemical markers of bone formation and bone resorption are available, and specific biochemical tests can be performed on blood or urine samples, but such markers of bone turnover have never been employed for age estimation in living individuals for forensic purposes. The aim of this study was to ascertain the applicability of serum bone alkaline phosphatase (BALP) concentration in the age estimation for forensic purposes. We focused on the legal age thresholds of 14 and 18 years (LAT) because, in Italy, the former is considered the minimum age for criminal responsibility and the latter defines adult age and the possibility of applying general criminal laws. MATERIALS AND METHODS: This study analyzed, from a forensic point of view, BALP and Tanner stages of 202 healthy white individuals (116 females and 86 males) between the ages of 10 and 30 years. We derived a linear logistic model to estimate the probability that an individual was older or younger than LAT using two variables: BALP concentration and Tanner stages. The predictive accuracy of the test was assessed by the determination of the receiver-operating characteristic curve (ROC curve). The test was performed to identify a threshold (cutoff) that could be used to assign an individual to the population of those younger or older than LAT. RESULTS: ROC curve showed that the use of both serum BALP concentration and Tanner stages has a very good level of reliability in age assessment (the area under the ROC curve, AUC, ranged from 0.918 to 0.962). Best results were obtained in the assessment of male over 18 years of age (sensibility and specificity respectively of 0.90 and 0.93 with an accuracy of 0.92). Worst results were obtained in the assessment of female over 18 years of age (sensibility and specificity respectively of 0.87 and 0.82 with an accuracy of 0.84). We also calculated the probability of the correctness in the age estimation. CONCLUSION: The results showed that the use of serum BALP concentration in the age assessment could be a promising and integrative method to established ones, but more research has to be done to validate the value of the proposed method in the forensic practice.

Tenofovir and bone: age-dependent effects in a zebrafish animal model.

BACKGROUND: New drugs against HIV infection are associated with important side effects, including impaired bone health. An important reduction of bone mineral density has been repeatedly described in adult but not in young patients receiving tenofovir disoproxil fumarate (TDF) as part of their antiretroviral regimen. The present study aimed to verify the presence and the characteristics of the adverse effects of TDF on skeletal tissue by using the Danio rerio (zebrafish) model. METHODS: TDF administration via microinjection in the yolk has been used for embryo study. Water treatment with TDF and scale analysis by morphological, histological and biochemical experiments have been used for adult animals. RESULTS: TDF administration via microinjection in the yolk did not induce any significant effect on mineralization rate and did not produce deformity of the skeletal structure, or growth or vitality impairment of the embryos. TDF exposure in adult zebrafish induced an age-related reduction of the osteoblastic activity marker alkaline phosphatase (up to -44%) and an increase of the osteoclastic activity marker tartrate-resistant acid phosphatase (up to +57%) in the scales. Old fish treated with TDF exhibited an osteoporotic-like phenotype with resorption area along the edge of the scale. CONCLUSIONS: This study demonstrated that in zebrafish, as in humans, TDF shows a catabolic bone effect related to age and underlined the ultimate utility of using teleost fish as a model to assess the effects of drugs on bone tissue.

Bone health in HIV-infected children and adolescents.

PURPOSE OF REVIEW: Chronic HIV infection and exposure to antiretroviral therapy compromises bone health in children and adolescents, potentially impacting their long-term quality of life. Thus, the purpose of this article is to review the most recent literature on this topic in HIV-infected children and adolescents. RECENT FINDINGS: Recent studies continue to demonstrate bone abnormalities in HIV-infected children and adolescents, whether HIV is acquired perinatally or during adolescence. Researchers have employed new modalities, both high tech and those that can be utilized in resource-limited settings, to better assess bone health. New data suggest that this population may also be experiencing an increase incidence of fractures, and they may not acquire the same peak bone mass as their HIV-uninfected counterparts. Reassuringly, however, in-utero tenofovir exposure does not appear to have a significant impact on bone health in HIV-exposed, uninfected infants. SUMMARY: HIV-infected children and adolescents are exposed to HIV and antiretroviral therapy for many decades starting early in life and during the most critical time for skeletal growth and bone mass accrual. Recent findings underscore the need for further research on bone in this population. Longitudinal studies are especially needed to evaluate long-term risk of osteoporosis and fracture.