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Objective: To describe the natural history of vitamin D deficiency in an at-risk population of African migrants living in Sydney.Design, Setting and Participants: Opportunistic study of 25-hydroxyvitamin D [25(OH)D] concentrations over time in a community-based cohort of North African refugee families living in south-western Sydney. As part of a health-screening program, serum concentrations of 25(OH)D, parathyroid hormone (PTH), calcium, phosphate (PO(4)) and alkaline phosphatase (ALP) were measured in September 2006 (end of winter, T1). Results for 25(OH)D were made available, and treatment was recommended as appropriate. In February-March 2007 (end of summer, T2), in the setting of a separate study of high-dose vitamin D (stoss) therapy, the same cohort was contacted, and measurements were repeated.Main Outcome Measures: Changes in 25(OH)D, PTH, ALP and PO(4) concentrations between T1 and T2 in those who had not received vitamin D supplementation in the intervening period.Results: We collected data from 149 participants at T1; by T2, 58 participants (39%) had been excluded or lost to follow-up. Data from 91 participants (46% female), all of whom had Type VI (very dark) skin pigmentation, were included in the analysis. All 91 were 25(OH)D deficient at T1. Between T1 and T2, mean 25(OH)D serum concentration increased from 19 nmol/L (SD, 5.6 nmol/L) to 36 nmol/L (SD, 12.4 nmol/L) (P < 0.001). Of the 91 participants, 79 (87%) remained vitamin D deficient at T2. Serum PTH and ALP activity decreased between T1 and T2 (P < 0.05).Conclusion: Despite a significant increase in 25(OH)D serum concentration over the study period, most participants (87%) remained 25(OH)D deficient at the end of summer. Our results support the current consensus that recommends annual screening for vitamin D deficiency and routine vitamin D supplementation in at-risk populations, such as dark-skinned or veiled groups. [ABSTRACT FROM AUTHOR]

An abstract of the study "Evaluation of Bone Mineral Density and Bone/Muscle Geometry Using pQCT in Children After Spinal Cord Injury" by C. F. Munns et al is presented.

Aim: This scoping review aims to expansively review the reporting of Indigenous status, ethnicity, culture, language and country of birth in Australian paediatric clinical studies., Methods: Scoping review of Australian clinical studies, including randomised controlled trials, non-randomised controlled trials, cluster randomised controlled trials and quasi-experimental studies, with paediatric participants (<18 years) or mixed adult and paediatric participants. PubMed, Cumulated Index to Nursing and Allied Health Literature and Embase databases were searched for clinical studies published 1 January 2018 to 28 November 2022., Results: Of the 2717 studies identified in the search, 209 clinical studies were included. Overall, 131 (62.7%) clinical studies captured in this review did not report any of the variables of interest. When reported, terms used by study authors varied extensively and subsequently five study-defined categories emerged 'Indigenous status', 'race', 'race and ethnicity', 'ethnicity', or 'natural skin colour'. 'Indigenous status' was most reported (n = 37, 17.7%), followed by 'ethnicity and/or cultural background' (n = 15, 7.2%), 'race and ethnicity' (n = 4, 1.9%), race (n = 1, 0.5%) and 'natural skin colour' (n = 1, 0.5%). Furthermore, language used at home was reported in 27 studies (12.9%) and country of birth in 23 studies (11.0%)., Conclusions: This review demonstrated very low reporting of Indigenous status, ethnicity, culture, language and country of birth in Australian paediatric clinical studies. Poor reporting has raised concerns surrounding generalisability of findings from these trials in addition to equity. The recent international shift encompassing improved clinical trial reporting requirements, for ethnicity and race, require prompt establishment in the Australian clinical trial domain., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

X-linked hypophosphataemia is a genetic disease caused by defects in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene and is characterised by X-linked dominant inheritance. The main consequence of PHEX deficiency is increased production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) in osteoblasts and osteocytes. Chronic exposure to circulating FGF23 is responsible for renal phosphate wasting and decreased synthesis of calcitriol, which decreases intestinal phosphate absorption. These mechanisms result in lifelong hypophosphataemia, impaired growth plate and bone matrix mineralisation, and diverse manifestations in affected children and adults, including some debilitating morbidities and possibly increased mortality. Important progress has been made in disease knowledge and management over the past decade; in particular, targeting FGF23 is a therapeutic approach that has substantially improved outcomes. However, patients affected by this complex disease need lifelong care and innovative treatment strategies, such as gene repair of PHEX, are necessary to further limit the disease burden., Competing Interests: Declaration of interests PK received payment or honoraria for lectures or educational events from Amolyt Pharma, Kyowa Kirin, and Pfizer; received support for attending meetings and travel from Amolyt Pharma, Pfizer, and Recordati; participated on advisory boards of Amolyt Pharma and Ascendis Pharma; and has served as clinical lead of the calcium and bone focus area of the European Society of Endocrinology since 2021. KB received consulting fees from Amgen and Kyowa Kirin; received payment or honoraria for lectures or educational events from Amgen, Kyowa Kirin, and Theramex; and participated on advisory boards of Amgen, Kyowa Kirin, and Theramex. CFM received consulting fees from Alexion and BioMarin; and payment or honoraria for lectures or educational events from BioMarin and Kyowa Kirin. AL received consulting fees from Alexion; received payment or honoraria for lectures or educational events from Kyowa Kirin, Novo Nordisk, and Pfizer; and currently serves as President of the French Society of Pediatrics., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Hypophosphatasia (HPP) is a rare, inherited, and systemic disorder characterized by impaired skeletal mineralization and low tissue nonspecific serum alkaline phosphatase (TNSALP) activity. It is caused by either autosomal recessive or dominant-negative mutations in the gene that encodes TNSALP. The phenotype of HPP is very broad including abnormal bone mineralization, disturbances of calcium and phosphate metabolism, pain, recurrent fracture, short stature, respiratory impairment, developmental delay, tooth loss, seizures, and premature death. Other than supportive care, there has been no disease-specific treatment available for those with HPP. Asfotase alfa is a fully humanized, recombinant enzyme replacement therapy for the management of HPP. It is available in several countries for the treatment of the more severe forms of HPP, namely perinatal and infantile HPP. This review will summarize the preclinical data on asfotase alfa and highlight the data from clinical trials and case reports. These data show the transformative nature of asfotase alfa when administered as part of an interdisciplinary treatment model., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO ® , BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023., Methods: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice., Results: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access., Conclusions: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available.

Neurofibromatosis type 1 (NF1) is a complex genetic disorder that affects a range of tissues including muscle and bone. Recent preclinical and clinical studies have shown that Nf1 deficiency in muscle causes metabolic changes resulting in intramyocellular lipid accumulation and muscle weakness. These can be subsequently rescued by dietary interventions aimed at modulating lipid availability and metabolism. It was speculated that the modified diet may rescue defects in cortical bone as NF1 deficiency has been reported to affect genes involved with lipid metabolism. Bone specimens were analyzed from wild type control mice as well as Nf1Prx1-/- (limb-targeted Nf1 knockout mice) fed standard chow versus a range of modified chows hypothesized to influence lipid metabolism. Mice were fed from 4 weeks to 12 weeks of age. MicroCT analysis was performed on the cortical bone to examine standard parameters (bone volume, tissue mineral density, cortical thickness) and specific porosity measures (closed pores corresponding to osteocyte lacunae, and larger open pores). Nf1Prx1-/- bones were found to have inferior bone properties to wild type bones, with a 4-fold increase in the porosity attributed to open pores. These measures were rescued by dietary interventions including a L-carnitine + medium-chain fatty acid supplemented chow previously shown to improve muscle histology function. Histological staining visualized these changes in bone porosity. These data support the concept that lipid metabolism may have a mechanistic impact on bone porosity and quality in NF1., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 O’Donohue et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Context: Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents., Objective: This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders., Participants: Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document., Evidence: Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available., Conclusion: Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate., Objective: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy., Methods: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] or calcitriol [30 ng/kg or less] (LD)., Results: At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses., Conclusion: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To describe changing primary care ordering of serum 25-hydroxyvitamin D (25OHD) tests in Australian children., Design: Longitudinal, population-based descriptive study of 25OHD testing using a large administrative dataset of pathology orders and results, 2003-2018., Setting and Participants: Three primary health networks in Victoria, Australia. Patients aged ≤18 years with a serum 25OHD test ordered by the general practitioner (GP)., Main Outcome Measures: Trends over 15 years in the number of 25OHD tests ordered, proportion indicating low levels or vitamin D deficiency and details of repeat testing., Results: Of 970 816 laboratory tests, 61 809 (6.4%) included an order for a 25OHD test. The 61 809 tests were performed in 46 960 children or adolescents. The odds of ordering a 25OHD test in 2018 was 30.4 times higher compared with 2003 (95%CI 22.6 to 40.8, p<0.001). The odds of detecting a low 25OHD (<50 nmol/L) compared with the baseline in 2003 remained steady (adjusted OR<1.5) over time. Repeat tests (14 849) were undertaken in 9626 patients (median intertest interval 357 days, IQR 172-669 days). A total of 4603 test results indicated vitamin D deficiency (<30 nmol/L), but in only 180 (3.9%) of these was a repeat test performed within 3 months as recommended., Conclusion: Testing volumes increased 30-fold, but the odds of detecting low 25OHD remained steady. Current Australian policy and the Global Consensus Recommendations for the prevention and management of nutritional rickets do not support routine 25OHD testing. Education and electronic pathology ordering tools may assist GPs to better align practice with current recommendations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: X-linked hypophosphataemia (XLH) is the most common heritable form of rickets. Prevalence data varies across the literature between 1 in 20,000 and 1 in 200,000 per population., Methods: Australian and New Zealand Paediatric Surveillance Units collected cross-sectional data from paediatricians on existing cases to estimate prevalence and characteristics of paediatric XLH in Australia and New Zealand., Results: Seventy-five cases in Australia and 18 cases in New Zealand were identified. Estimated minimum prevalence based on these cases was 1.33 (1.04-1.66) per 100,000 and 1.60 per 100,000 (95%CI 0.97-2.58) in Australia and New Zealand respectively, with actual prevalence likely higher due to incomplete ascertainment. Despite a family history in most cases, delayed diagnosis was common, with 49 % diagnosed after 2 years of age. Delayed diagnosis was more common in sporadic versus familial cases. Most common clinical characteristics included leg bowing (89 %), bone and joint pain (68 %), abnormal gait (57 %) and short stature (49 %). There was a significant burden of orthopaedic disease and surgeries and a high rate of complications of nephrocalcinosis and hyperparathyroidism (32 % and 20 % respectively). Additionally, while guidelines stress the importance of multidisciplinary care, many did not have access to recommended health professionals, with only 3 % seeing a psychologist and 68 % seeing a dentist. This is despite the high psychological burden of XLH and a significant proportion (41 %) of this cohort having dental issues (tooth abscess, dental capping, tooth extraction). There were two cases from NZ without data available. Of the 91 cases with data collected, 46 % were on burosumab therapy. Consistent with clinical trials, those on burosumab had a higher serum phosphate levels (p < 0.001) at most recent follow-up. Three cases reported cancellation of orthopaedic surgery due to improvement in lower limb deformity after commencement of burosumab., Conclusion: These data describe the multisystem burden of disease for children with XLH with care impacted by delayed diagnosis and a lack of access to many health professionals, especially psychological support., Competing Interests: Declaration of competing interest This study was financially supported by Kyowa Kirin. Australia and New Zealand Society of Paediatric Endocrinology and Diabetes (ANZSPED) XLH Writing Group (JS, CM, AB, AS, PS, CR) participate in research funded by Kyowa Kirin. PS, AB, AS and CM have been on advisory boards and accepted speaker fees from Kyowa Kirin., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A multivariable logistic regression model resulting from a case-control study of nutritional rickets in Nigerian children suggested that higher levels of serum 25(OH)D may be required to prevent nutritional rickets in populations with low-calcium intakes., Objectives: This current study evaluates if adding serum 1,25-dihydroxyvitamin D [1,25(OH) 2 D] to that model shows that increased levels of serum 1,25(OH) 2 D are independently associated with risk of children on low-calcium diets having nutritional rickets., Methods: Multivariable logistic regression analysis was used to model the association between serum 1,25(OH) 2 D and risk of having nutritional rickets in cases (n = 108) and controls (n = 115) after adjusting for age, sex, weight-for age z-score, religion, phosphorus intake and age began walking and the interaction between serum 25(OH)D and dietary calcium intake (Full Model)., Results: Serum 1,25(OH) 2 D levels were significantly higher (320 pmol/L vs. 280 pmol/L) (P = 0.002), and 25(OH)D levels were lower (33 nmol/L vs. 52 nmol/L) (P < 0.0001) in children with rickets than in control children. Serum calcium levels were lower in children with rickets (1.9 mmol/L) than in control children (2.2 mmol/L) (P < 0.001). Dietary calcium intakes were similarly low in both groups (212 mg/d) (P = 0.973). In the multivariable logistic model, 1,25(OH) 2 D was independently associated with risk of having rickets [coefficient = 0.007 (95% confidence limits: 0.002-0.011)] after adjusting for all variables in the Full Model., Conclusions: Results confirmed theoretical models that in children with low dietary calcium intake, 1,25(OH) 2 D serum concentrations are higher in children with rickets than in children without rickets. The difference in 1,25(OH) 2 D levels is consistent with the hypothesis that children with rickets have lower serum calcium concentrations which prompt the elevation of PTH levels resulting in an elevation of 1,25(OH) 2 D levels. These results support the need for additional studies to identify dietary and environmental risks for nutritional rickets., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m 2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol., (© 2023. Crown.)

Background: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19)., Methods: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline., Results: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified., Conclusions: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.)., (Copyright © 2023 Massachusetts Medical Society.)

Osteogenesis imperfecta (OI) is a genetic bone fragility disorder that features frequent fractures. Bone healing outcomes are contingent on a proper balance between bone formation and resorption, and drugs such as bone morphogenetic proteins (BMPs) and bisphosphonates (BPs) have shown to have utility in modulating fracture repair. While BPs are used for OI to increase BMD and reduce pain and fracture rates, there is little evidence for using BMPs as local agents for fracture healing (alone or with BPs). In this study, we examined wild-type and OI mice (Col1a2 +/G610C ) in a murine tibial open fracture model with (i) surgery only/no treatment, (ii) local BMP-2 (10 µg), or (iii) local BMP-2 and postoperative zoledronic acid (ZA; 0.1 mg/kg total dose). Microcomputed tomography reconstructions of healing fractures indicated BMP-2 was less effective in an OI setting, however, BMP-2 +ZA led to considerable increases in bone volume (+193% WT, p < 0.001; +154% OI, p < 0.001) and polar moment of inertia (+125% WT, p < 0.01; +248% OI, p < 0.05). Tissue histology revealed a thinning of the neocortex of the callus in BMP-2 treated OI bone, but considerable retention of woven bone in the healing callus with BMP + ZA specimens. These data suggest a cautious approach may be warranted with the sole application of BMP-2 in an OI surgical setting as a bone graft substitute. However, this may be overcome by off-label BP administration., (© 2022 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: SW was an employee of Kyowa Kirin International at the time of writing. AW is an employee of Kyowa Kirin International. CFM has received consultant fees, speaker fees, a travel grant, and a research grant from Kyowa Kirin. AB has received consultant fees and a research grant from Kyowa Kirin., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Purpose: The creation of murine gene knockout models to study bone gene functions often requires the resource intensive crossbreeding of Cre transgenic and gene-floxed strains. The developmental versus postnatal roles of genes can be difficult to discern in such models. For example, embryonic deletion of the Sclerostin (Sost) gene establishes a high-bone mass phenotype in neonatal mice that may impact on future bone growth. To generate a postnatal skeletal knockout of Sost in adult mice, this study used a single injection of a bone-targeted recombinant adeno-associated virus (rAAV) vector., Methods: 8-week-old Sost flox/flox mice were injected with saline (control) or a single injection containing 5 × 10 11 vg AAV8-Sp7-Cre vector. Ai9 fluorescent Cre reporter mice were dosed in parallel to confirm targeting efficiency. After 6 weeks, detailed bone analysis was performed via microCT, biomechanical testing, and bone histology on vertebral and long bone specimens., Results: The AAV8-Sp7-Cre vector induced widespread persistent recombination in the bone compartment. Regional microCT analyses revealed significant increases in bone with vector treatment. In the L3 vertebrae, Sost flox/flox :AAV-Cre showed a 22 % increase in bone volume and 21 % in trabecular bone fraction compared to controls; this translated to a 17 % increase in compressive strength. In the tibiae, Sost flox/flox :AAV-Cre led to small but statistically significant increases in cortical bone volume and thickness. These were consistent with a 25 % increase in mineral apposition rate, but this did not translate into increased four-point bending strength. Ploton silver nitrate stain on histological sections revealed an unexpected increase in canalicular density associated with Sost ablation., Conclusion: This report demonstrates a proof-of-concept that the AAV8-Sp7-Cre vector can efficiently produce postnatal skeletal knockout mice using gene-floxed strains. This technology has the potential for broad utility in the bone field with existing conditional lines. These data also confirm an important postnatal role for Sost in regulating bone homeostasis, consistent with prior studies using neutralizing Sclerostin antibodies, and highlights a novel role of Sost in canalicular remodeling., Competing Interests: Declaration of competing interest Generation of the Sost(flox/flox) mouse line was enabled by funding from the National Health and Medical Research Council (Australia) by GNT1066357. Philanthropy support was given by the Sydney Children's Hospital's Foundation and the Teicke Foundation., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

This pilot study explored the feasibility and effectiveness of vibration therapy (VT) on muscle and bone health, motor performance, and respiratory function in patients with congenital myopathy (CM). Eleven participants with CM (11.5 ± 2.8 years) underwent 12 weeks of side-alternating VT at 20 Hz for nine minutes per session, four days a week. VT was preceded by a 12-week control period. Assessments included dual-energy X-ray absorptiometry scans, 6-minute walk and 10-meter run tests, muscle function and motor performance assessment, dynamometry, and pulmonary function. VT was well-tolerated, with occasional mild itchiness reported. The median compliance level with VT treatment was 75%. 12 weeks of VT improved the total score of motor function performance by 2.4 units (p=0.006) and velocity rise maximum of the chair rising test by 0.11 m/s (p=0.029). VT was shown to be feasible, safe, and associated with improving motor function performance. Our findings support further exploration of VT's potential health benefits to patients with CM in larger studies involving a longer intervention period., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To describe bone mineral density (BMD), bone structure, and fracture prevalence in adolescents with type 1 diabetes (T1D) and explore their associations with glycemic control and microvascular complications., Research Design and Methods: Cross sectional study of 64 adolescents (38 males) with T1D duration >10 years who underwent dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), fracture survey, plantar fascia thickness, and microvascular complications assessment., Results: Mean age was 16.6 ± 2.1 years, diabetes duration 12.8 ± 2.2 years and HbA1c 8.9 ± 1.7% (74 mmol/mol). Fracture prevalence was 50%. DXA areal BMD (Z-score) was reduced for femoral neck (-0.5 ± 1.3, p = 0.008) and arm (-0.4 ± 1.0, p < 0.001), while total areal BMD and lumbar spine BMD were normal. In pQCT (Z-score), trabecular volumetric BMD (vBMD) was reduced for tibia (-0.4 ± 0.8, p < 0.001) and radius (-0.8 ± 1.4, p < 0.001) whereas cortical vBMD was increased at both sites (tibia: 0.5 ± 0.6, p < 0.001, radius: 0.7 ± 1.5, p < 0.001). Muscle cross-sectional area (CSA) was reduced for upper (-0.6 ± 1.2, p < 0.001) and lower (-0.4 ± 0.7, p < 0.001) limbs. DXA total areal BMD was positively correlated with BMI (p < 0.01) and age at T1D diagnosis (p = 0.04). Lower radial bone CSA, total and lumbar spine BMD were associated with autonomic nerve dysfunction. HbA1c, diabetes duration, fracture history and other microvascular complications were not significantly associated with bone parameters., Conclusions: Adolescents with childhood-onset T1D have site-specific bone deficits in upper and lower limbs but normal total and lumbar spine BMD. T1D appears to have differential effects on trabecular and cortical bone compartments. Future longitudinal analysis is warranted to examine whether these changes translate in to increased fracture risk., (© 2022 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Context: Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown., Objective: This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH., Methods: This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64., Results: The LSMD in outcomes through 64 weeks on burosumab vs conventional therapy by age group were as follows: RGI-C rickets total score (younger, +0.90; older, +1.07), total Rickets Severity Score (younger, -0.86; older, -1.44), RGI-C lower limb deformity score (younger, +1.02; older, +0.91), recumbent length or standing height Z-score (younger, +0.20; older, +0.09), and serum alkaline phosphatase (ALP) (younger, -31.15% of upper normal limit [ULN]; older, -52.11% of ULN). On burosumab, dental abscesses were not reported in younger children but were in 53% of older children., Conclusion: Burosumab appears to improve outcomes both in younger and older children with XLH, including rickets, lower limb deformities, growth, and ALP, compared with Pi/D., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Osteogenesis imperfecta (OI) or brittle bone disease is a genetic disorder that results in bone fragility. Bisphosphonates such as zoledronic acid (ZA) are used clinically to increase bone mass and reduce fracture risk. Human growth hormone (hGH) has been used to promote long bone growth and forestall short stature in children with OI. The potential for hGH to improve bone quality, particularly in combination with ZA has not been robustly studied., Methods: A preclinical study was performed using n = 80 mice split evenly by genotype (WT, Col1a2 +/G610C ). Groups of n = 10 were treated with +/-ZA and +/-hGH in a factorial design for each genotype. Outcome measures included bone length, isolated muscle mass, bone parameters assessed by microCT analysis, dynamic histomorphometry, and biomechanical testing., Results: Treatment with hGH alone led to an increase in femur length in WT but not OI mice, however bone length was increased in both genotypes with the combination of hGH/ZA. MicroCT showed that hGH/ZA treatment increased cortical BV in both WT (+15%) and OI mice (+14.3%); hGH/ZA were also found to be synergistic in promoting cortical thickness in OI bone. ZA was found to have a considerably greater positive impact on trabecular bone than hGH. ZA was found to suppress bone turnover, and this was rescued by hGH treatment in terms of cortical periosteal perimeter, but not by dynamic bone remodeling. Statistically significant improvements in long bone by microCT did not translate into improvements in mechanical strength in a 4-point bending test, nor did vertebral strength improve in L4 compression testing in WT/OI bone., Discussion/conclusion: These data support hGH/ZA combination as a treatment for short stature, however the improvements granted by hGH alone and in combination with ZA on bone quality are modest. Increased periosteal perimeter does show promise in improving bone strength in OI, however a longer treatment time may be required to see effects on bone strength through mechanical testing., (Copyright © 2022. Published by Elsevier Inc.)

Background: Central giant cell granulomas (CGCG) are rare osteolytic, benign but often locally aggressive tumours of bone. Surgical curettage may not be possible in extensive lesions and resection carries high morbidity, especially in growing children, and previous medical therapies have had variable efficacy and high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours., Aims: To evaluate the efficacy and safety of our protocol for denosumab treatment of CGCG in children., Methods: Retrospective review of 4 patients treated with denosumab using a standardised protocol for CGCG in a tertiary paediatric centre. Denosumab 70 mg/m 2 was given 4-weekly, followed by 2 doses of zoledronate 0.025 mg/kg, aimed at preventing rebound hypercalcaemia., Results: Treatment of CGCG resulted in metabolic remission in all patients, but recurrence, detected by positron emission tomography (PET), occurred at 6 months in three patients and 12 months in one patient. Three patients developed symptomatic hypercalcaemia 4-5 months and one patient asymptomatic hypercalcaemia 7 months after cessation of denosumab, with 3 requiring additional bisphosphonate treatment., Conclusions: Denosumab produced a radiological and metabolic response in our patients, but metabolic recurrence occurred in all patients. PET imaging was effective for monitoring treatment response and early detection of recurrence. Incidence of rebound hypercalcaemia in this paediatric cohort was high. We present proposed changes to our protocol with the aim of producing sustained remission and preventing rebound hypercalcaemia., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

X-linked hypophosphataemia (XLH), the most common inherited form of rickets, is caused by a PHEX gene mutation that leads to excessive serum levels of fibroblast growth factor 23 (FGF23). This leads to clinical manifestations such as rickets, osteomalacia, pain, lower limb deformity and overall diminished quality of life. The overarching aims in the management of children with XLH are to improve quality of life by reducing overall burden of disease, optimise an individual's participation in daily activities and promote normal physical and psychological development. Burosumab, a monoclonal antibody targeting FGF23, has been shown to improve biochemistry, pain, function and radiological features of rickets in children with XLH and has transformed management of XLH around the world. Burosumab has been recently approved for clinical use in children with XLH in Australia. This manuscript outlines a clinical practice guideline for the use of burosumab in children with XLH to assist local clinicians, encourage consistency of management across Australia and suggest future directions for management and research. This guideline also strongly advocates for all patients with XLH to have multidisciplinary team involvement to ensure optimal care outcomes and highlights the need to consider other aspects of care for XLH in the era of burosumab, including transition to adult care and the effective coordination of care between local health-care providers and specialist services., (© 2022 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Osteogenesis imperfecta (OI) describes a series of genetic bone fragility disorders that can have a substantive impact on patient quality of life. The multidisciplinary approach to management of children and adults with OI primarily involves the administration of antiresorptive medication, allied health (physiotherapy and occupational therapy), and orthopedic surgery. However, advances in gene editing technology and gene therapy vectors bring with them the promise of gene-targeted interventions to provide an enduring or perhaps permanent cure for OI. This review describes emergent technologies for cell- and gene-targeted therapies, major hurdles to their implementation, and the prospects of their future success with a focus on bone disorders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Central giant cell granuloma (CGCG) is a rare lesion of the jaw occurring in young adults and adolescents. Surgery, the traditional mainstay of therapy, is associated with significant morbidity. Denosumab, a humanised monoclonal antibody to RANKL, is effective in a related entity, giant cell tumour of bone (GCTB), but experience in the more indolent CGCG is limited. This prospective observational study of all denosumab-treated CGCG at a tertiary referral centre (2015-2021) aimed to evaluate the safety, efficacy and recurrence risk using denosumab in CGCG at lower-frequency dosing than used for GCTB. All received standardised, time-limited courses of denosumab 120 mg with stepwise increase in dosing interval based on response. They were followed for up to 75 months using a radiation-minimising protocol: 3-monthly clinical, biochemical and radiological assessment (orthopantomograms, cone beam CT). Eight patients, median age 20.5 years [IQR 6], received 13 initial doses [IQR 10] of denosumab 120 mg. Radiologic response was seen after 5.5 doses [IQR 4.5]: ossification in all and size reduction in three. Recurrence occurred in four of seven completing therapy, observed 12 months post-cessation [IQR 6.5]. Larger baseline size, aggressive subtype and fewer than 12 initial doses were more common in the recurrence group. There was no osteonecrosis of the jaw. Hypocalcaemia occurred in one receiving modified dosing. This study represents the largest, most diverse cohort of denosumab-treated CGCG with the longest follow-up in literature. It demonstrates the efficacy of lower-frequency, time-restricted course of denosumab but highlights the risk of recurrence. Long-term follow-up is critical., (© 2021. Crown.)

Context: Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures., Objective: This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO)., Methods: Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed., Results: Thirty-four children were enrolled (mean age 12.6 ± 3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ± 0.79 to -1.49 ± 1.05 on ZA, compared with -2.38 ± 0.90 to -2.27 ± 1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs., Conclusion: LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7 R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases., (© 2021. The Author(s).)

Introduction: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19., Methods and Analysis: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections., Ethics and Dissemination: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system., Trial Registration: ClinicalTrials.gov NCT04327206., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Context: Nutritional rickets results from the interaction of low vitamin D status and limited calcium intake. Serum alkaline phosphatase (AP) activity is a biomarker of impaired mineralization in rickets., Objective: To assess the performance of serum AP activity in identifying nutritional rickets in calcium-deprived Nigerian children., Methods: We reanalyzed data from a case-control study of children with active rickets and matched control subjects without rickets, using a multivariate logistic regression to assess the odds of rickets associated with AP activity, adjusting for age, sex, and weight-for-age z-score., Results: A total of 122 children with rickets and 119 controls were included. Rachitic children had a mean (±SD) age of 54 ± 29 months, and 55 (45.1%) were male. Cases and controls had low dietary calcium intakes (216 ± 87 and 214 ± 96 mg/day, respectively). Serum AP activity levels in cases and controls were 812 ± 415 and 245 ± 78 U/L, respectively (P < 0.001). AP was negatively associated with 25-hydroxyvitamin D values (r = -0.34; P < 0.001). In the adjusted model, the odds ratio (95% CI) receiver operating characteristic curve was 0.978. AP > 350 U/L identified nutritional rickets in Nigerian children with sensitivity 0.93, specificity 0.92, positive likelihood ratio 11.3, and negative likelihood ratio 0.07., Conclusion: An AP > 350 U/L effectively discriminated between Nigerian children with and without nutritional rickets. AP is a low-cost biochemical test that could be used to screen for nutritional rickets, but cutoff values require validation in other populations, and laboratory values need to be standardized for widespread population studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is substantial evidence that adults with type 1 diabetes have reduced bone mineral density (BMD); however, findings in youth are inconsistent., Purpose: To perform a systematic review and meta-analysis of BMD in youth with type 1 diabetes using multiple modalities: DXA, peripheral quantitative computed tomography (pQCT), and/or quantitative ultrasound (QUS)., Data Sources: PubMed, Embase, Scopus, and Web of Science from 1 January 1990 to 31 December 2020, limited to humans, without language restriction., Study Selection: Inclusion criteria were as follows: cross-sectional or cohort studies that included BMD measured by DXA, pQCT, or QUS in youth (aged <20 years) with type 1 diabetes and matched control subjects., Data Extraction: We collected data for total body, lumbar spine, and femoral BMD (DXA); tibia, radius, and lumbar spine (pQCT); and phalanx and calcaneum (QUS). Weighted mean difference (WMD) or standardized mean difference was estimated and meta-regression was performed with age, diabetes duration, and HbA 1c as covariates., Data Synthesis: We identified 1,300 nonduplicate studies; 46 met the inclusion criteria, including 2,617 case and 3,851 control subjects. Mean ± SD age was 12.6 ± 2.3 years. Youth with type 1 diabetes had lower BMD: total body (WMD -0.04 g/cm 2 , 95% CI -0.06 to -0.02; P = 0.0006), lumbar spine (-0.02 g/cm 2 , -0.03 to -0.0; P = 0.01), femur (-0.04 g/cm 2 , -0.05 to -0.03; P < 0.00001), tibial trabecular (-11.32 g/cm 3 , -17.33 to -5.30; P = 0.0002), radial trabecular (-0.91 g/cm 3 , -1.55 to -0.27; P = 0.005); phalangeal (-0.32 g/cm 3 , -0.38 to -0.25; P < 0.00001), and calcaneal (standardized mean difference -0.69 g/cm 3 , -1.11 to -0.26; P = 0.001). With use of meta-regression, total body BMD was associated with older age (coefficient -0.0063, -0.0095 to -0.0031; P = 0.002) but not with longer diabetes duration or HbA 1c ., Limitations: Meta-analysis was limited by the small number of studies with use of QUS and pQCT and by lack of use of BMD z scores in all studies., Conclusions: Bone development is abnormal in youth with type 1 diabetes, assessed by multiple modalities. Routine assessment of BMD should be considered in all youth with type 1 diabetes., (© 2021 by the American Diabetes Association.)

Context: Patients with glucocorticoid-dependent Duchenne muscular dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss., Objective: To investigate use of zoledronic acid (ZA) in DMD in improving BMD., Methods: Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, peripheral quantitative computerized (pQCT) and pain scores., Results: At 12 and 24 months, mean difference in changes of LS BMD Z-score from baseline was 1.2 SD (95% CI 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA than control arms respectively (both P < .001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain, and bone turnover markers were similar between arms at 12 and 24 months. Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort than control; the evidence for this difference remained at 24 months for radius but not tibia., Conclusion: ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nutritional rickets is believed to result from the interaction of inadequate serum 25-hydroxyvitamin D [25(OH)D] concentration and dietary calcium intake, but this interaction has not been confirmed in children with rickets. Determining the vitamin D requirements to prevent nutritional rickets has been thwarted by inconsistent case definition, inadequate adjustment for calcium intake and other confounders, and 25(OH)D assay variability., Objectives: To model the 25(OH)D concentration associated with nutritional rickets in calcium-deprived Nigerian children, adjusted for confounding factors, and develop a general approach to define vitamin D status while accounting for calcium intake., Methods: Logistic regression was used to model the association of serum 25(OH)D with having rickets adjusted for calcium intake in a reanalysis of a case-control study in Nigerian children. The matching variables age, sex, weight-for-age z score, and 4 additional significant variables were selected [religion, age began walking, phosphorus intake, and the 25(OH)D × calcium intake interaction] using a rigorous 7-step algorithm., Results: Cases had significantly (P < 0.0001) lower mean ± SD 25(OH)D than controls (33 ± 13 compared with 51 ± 16 nmol/L, respectively), whereas cases and controls had similarly (P = 0.81) low mean dietary calcium intakes (216 ± 88 and 213 ± 95 mg/d, respectively). There was a significant interaction between 25(OH)D and calcium intake [coefficient (95% CI): -0.0006 (-0.0009, -0.0002)]. Accordingly, as calcium intake increased from 130 to 300 mg/d, the adjusted odds of having rickets decreased dramatically with increasing 25(OH)D such that at 200 mg/d, the adjusted odds of having rickets at 47.5 nmol/L was 0.80, whereas it was 0.2 at 62.5 nmol/L. Moreover, at a calcium intake of 300 mg/d, the adjusted odds was 0.16 at a 25(OH)D concentration of 47.5 nmol/L and 0.02 at 62.5 nmol/L., Conclusions: The vitamin D requirement to prevent nutritional rickets varies inversely with calcium intake and vice versa. Also, application of multivariable modeling is essential in defining vitamin D requirements., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective and Background: Secondary adrenal insufficiency (SAI) is a rare condition in childhood which can be associated with high levels of morbidity in some patients. The causes of increased levels of illness are not well defined and warrant further investigation., Methods: A retrospective cohort of patients with SAI was constructed by examining records of all attendances for acute illness by SAI patients at the emergency department of the two specialist paediatric hospitals in Sydney, Australia between 2004 and 2016. Demographic, clinical, and physiological characteristics together with pre-hospital illness management strategies were assessed., Results: There were 168 presentations for an acute illness by 47 children with SAI. Comorbid diabetes insipidus (DI) was present in 46.8% (n = 22), 77.3% (n = 17) of whom were male (P < .05). Patients with comorbid DI were more likely to be admitted (86.7%, n = 65 vs 60.2%, n = 56 for non-DI, P < .01); had a longer hospital stay (6.5 (8.7) vs 2.5 (2.6) days, P < .001); and higher rates of IV HC administration (56.0%, n = 42 vs 35.5%, n = 33), P < .01). The medically-diagnosed adrenal crisis (AC) rate was 3.68 ACs/100PY. Stress dose use was reported by fewer DI patients (58.7%, n = 44) than non-DI patients (78.5%, n = 73, P < .01). Previous attendance at hospital was positively associated with stress dose use (OR = 1.08, 95% CI 1.00, 1.16)., Conclusion: Secondary adrenal insufficiency can cause significant morbidity in children. Comorbid DI is associated with higher levels of hospitalisation, longer hospital stays and lower levels of pre-emergent stress dose use. Educational interventions in this subgroup of SAI patients may reduce the burden of morbidity., (© 2021 John Wiley & Sons Ltd.)