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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.)

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.)

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.)

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia., Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705., Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved., Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy., Funding: Ultragenyx Pharmaceutical and Kyowa Kirin International., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The investigation of skeletal health data beyond dual X-ray absorptiometry (DXA) is limited in young individuals with CF. We assessed volumetric bone mineral densities (BMD), and bone and muscle parameters using peripheral quantitative computed tomography (pQCT) in individuals with CF and controls, 7.00-17.99 years., Methods: Peripheral QCT (XCT 3000, Stratec) measurements were made in 53 individuals with CF and 53 controls. Bone mineral content (BMC), total volumetric BMD (vBMD) and cross sectional area (CSA) of the bone were measured at the 4% and 66% sites of the non-dominant tibia and radius. Additionally, trabecular vBMD and bone strength index (BSIc) were measured at the 4% sites, and cortical vBMD, muscle CSA (mCSA) and strength strain index (SSI) were measured at the 66% sites., Results: Pre-pubertal males with CF had greater trabecular vBMD (p=0.01) and total vBMD (p=0.00) at 4% tibia, and greater total vBMD (p=0.02) at 4% radius. Pre-pubertal females with CF had greater total vBMD at 66% tibia (p=0.02) and radius (p=0.04), and cortical vBMD (p=0.04) at the radius. At puberty, the CF cohort had less BMC at 4% tibia (males, p=0.02; females, p=0.01), and smaller mCSA at 66% tibia (males, p=0.02; females, p=0.01). Pubertal CF females had a smaller bone CSA (p=0.01) at 4% tibia, and lower bone strength (SSI) at the tibia (p=0.00) and radius (p=0.05) sites., Conclusions: Bone strength parameters were not compromised prior to puberty in this CF cohort. At puberty, the bone phenotype changed for this CF cohort, showing several deficits compared to the controls. However, bone strength was adapting to the mechanical demands of the muscle. Altered bone parameters and their implications for lowered bone strength with increased age may be greatly influenced by: the CF cohort remaining smaller for age and/or a reduced bone strain, secondary to reduced muscle force., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: A suboptimal bone accrual in young individuals with cystic fibrosis (CF) may be related to the development of a premature CF-related bone disease. Dual energy X-ray absorptiometry (DXA) is the mainstream measure of bone health; however, the influence of body size and lean tissue mass (LTM) on bone data is poorly interpreted., Methods: Total body dual-energy X-ray absorptiometry (DXA) measurements of bone mineral content (BMC) and LTM in 53 individuals with CF (7.00-17.99years) were compared to 53 sex-matched controls. BMC, height, and LTM in relation to height and BMC Z-scores were calculated and used in a 4-step algorithm., Results: Pubertal females with CF had less total body BMC for age (p=0.02); pre-pubertal males (p=0.05) and pubertal females with CF (p=0.03) were shorter; and pubertal females with CF showed less total body BMC for LTM (p=0.01)., Conclusions: The algorithm showed the following: (1) prior to puberty lowered total body BMC was primarily due to short stature, (2) LTM was appropriate for body size, and (3) pubertal females with CF had significantly less total body BMC for their LTM. Longer controlled trials are needed to clinically interpret CF-related bone disease using DXA derived data that considers patient size and body composition., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease., Methods: In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028., Findings: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events., Interpretation: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta., Funding: Alliance for Better Bone Health (Warner Chilcott and Sanofi)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)