Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab.

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.

Randomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy.

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.

Risk of Fractures and Other Injuries in Children Treated with Antiseizure Medications for Epilepsy.

This study aimed to investigate the prevalence of fractures and non-fracture injuries, including associated risk factors, in children with epilepsy prescribed antiseizure medications (ASM). A controlled, cross-sectional study was conducted in a hospital outpatient setting, comparing children with epilepsy prescribed ASMs with their non-epileptic siblings. Information was collected by questionnaire included history of fractures, non-fracture injuries and epilepsy, comorbidities and ASM use. 261 participants completed the questionnaire, 133 children with epilepsy (aged 10.7 ± 3.5 years, mean ± SD) and 128 siblings (10.1 ± 3.7 years). There were 49 non-seizure-related fractures in 34 ASM patients while prescribed ASMs, compared with 21 lifetime fractures in 15 controls, giving a 2.7 (95% CI 1.3-5.3, p = 0.007) times greater fracture prevalence in children treated with ASMs compared to healthy siblings. The rates of non-fracture injuries were similar across groups, except that concussion was more common in children taking ASMs (9.0% vs 1.6%, p = 0.026). Duration of ASM use and generalized tonic-clonic seizures (GTCS) were independent predictors of fractures (OR 1.55; 95% CI 1.03-2.31, p = 0.03; OR 2.50; 95% CI 1.05-5.94, p = 0.04, respectively). Fewer than 20% of participants and/or their families were aware that ASM use was related to bone health. Children with epilepsy treated with ASMs had a higher fracture prevalence than their sibling controls. Duration of ASM treatment and GTCS were associated with fracture risk. Longitudinal prospective studies are required to further explore risk and the direct impact of epilepsy on bone health.

The clinical features that contribute to poor bone health in young Australians living with cystic fibrosis: A recommendation for BMD screening.

BACKGROUND: For Australians living with cystic fibrosis (CF), increased longevity means greater consideration needs to be given to long-term endocrine sequelae such as CF-related bone disease. Deficits in bone mass accrual are most likely to occur during childhood and adolescence. Current guidelines in Australia suggest repeat dual-energy X-ray absorptiometry (DXA) scans every 2 years. This study aims to stratify clinical factors that determine future bone health in the Australian CF population and use this to guide a more streamlined approach to bone health screening. METHODS: This study was a retrospective audit of all patients diagnosed with CF who were treated at the Royal Children's Hospital Melbourne, Australia from 2000 to 2016 (n = 453). Two hundred and two patients had a DXA scan in the study period (191 with height-adjusted data) and 111 patients had more than one scan (108 with height-adjusted data). An investigation into the associations between bone mineral density (BMD) Z score and potential risk factors was conducted using DXA and historical data. RESULTS: The main predictor of future BMD was the previous BMD Z score (p < .001). Other factors found to be determinants of BMD included nutritional status, lung function (FEV1 ), age, history of previous fracture, oral corticosteroid use, and the number of hospital admissions. However, after adjusting for previous BMD, evidence of an association remained only with nutritional status, FEV1 , and number of hospital admissions. CONCLUSION: Second yearly scans may be unnecessary in children with an adequate DXA score on the initial scan who remain clinically stable. However, clinical deterioration in those whose BMD was previously normal, may require closer monitoring of bone health. We propose a guideline for the frequency of DXA monitoring in relation to clinical risk factors.

Effect of Testosterone Treatment for Delayed Puberty in Duchenne Muscular Dystrophy.

OBJECTIVE: To evaluate the impact of pubertal induction with testosterone on bone health, body composition, and motor function in boys with Duchenne muscular dystrophy (DMD) receiving long-term glucocorticoid. STUDY DESIGN: A retrospective, observational, pre-post study investigating the impact of testosterone therapy on bone mass accrual, vertebral fracture incidence, body composition, motor function, and quality of life in boys with DMD. All those boys aged ≥14 years, on chronic steroid therapy, who had delayed puberty, and were receiving oral testosterone or oral and then transitioned to intramuscular testosterone, to complete virilization, were included. Prior/concomitant zoledronic acid use was included. The primary outcome was lumbar spine areal bone mineral density (BMD LS). RESULTS: Puberty was induced, using oral testosterone undecanoate in 16 individuals, 10 of whom had transited to intramuscular testosterone at time of assessment. Median age at testosterone onset was 14.5 years (range 14-17.7). Median duration of testosterone therapy was 2.5 years (range 1.0-4.5). There was statistically significant increase in median BMD LS (0.523-0.700, p < 0.001) and median annualized percentage change of BMD LS (-1.34 to +10.08%, p < 0.001), with median Tanner stage 4 at evaluation (range 2-4). Ten of 14 assessed had no progression in vertebral fractures. Fat mass index (FMI) standard deviation score (SDS), lean body mass index (LBMI) SDS, and percentage change of FMI and LBMI were statistically unchanged. Cardiac function remained stable. Motor function in non-ambulatory individuals with Egen Klassifikation scores improved in 7 of 8. CONCLUSION: Testosterone for delayed puberty acted as an adjunct to bisphosphonates to increase bone density and stabilize vertebral fracture in most boys with DMD.

Outcomes of Zoledronic Acid Use in Paediatric Conditions.

INTRODUCTION: Limited evidence is available concerning experience with use of zoledronic acid (ZA) and treatment for conditions other than primary bone fragility. MATERIALS AND METHODS: A retrospective review of all Royal Children Hospital patients who had been administered at least 1 dose of intravenous ZA from 2002 to 2015 was undertaken. RESULTS: The audit included 309 children with 228 being treated for bone fragility conditions. Of the 228, 68 had height-adjusted lumbar spine bone mineral density Z-scores available over up to a 5-year period, and median increases were +2.0 SD (median absolute deviation = 0.9) (N = 36, p value for median increase of at least 0.5 in Z-score <0.001), for patients with osteogenesis imperfecta or other primary bone fragility disorders, +1.0 SD (0.9) (N = 14, p = 0.029), for immobility conditions, +0.5 SD (0.7) (N = 10, p = 0.399), and for glucocorticoid-induced secondary osteoporosis, +0.7 SD (0.6) (N = 8, p = 0.015). 81/309 children were treated for bone abnormality indications (e.g., avascular necrosis [AVN], fibrous dysplasia, and bone cysts). Of 39 with AVN, outcome data were available for 33, with joint integrity maintained for 24/33 from 6 to 24 months after last ZA, subjective reports (22/28) of reduced pain. Reduction in bone lesion size was seen in 2/4 patients with bone cysts within 12 months of ZA commencement. DISCUSSION/CONCLUSION: This is the largest cohort of reported outcomes of ZA use in a paediatric population. Results demonstrate a good efficacy profile and associated improved bone density for osteoporotic conditions and stabilization of non-traumatic AVN with a low rate of joint collapse.

pQCT bone geometry and strength: population epidemiology and concordance in Australian children aged 11-12 years and their parents.

OBJECTIVES: To describe the epidemiology and concordance of bone health in a population-based sample of Australian parent-child dyads at child age 11-12 years. DESIGN: Population-based cross-sectional study (the Child Health CheckPoint) nested between waves 6 and 7 of the Longitudinal Study of Australian Children (LSAC). SETTING: Assessment centres in seven cities around Australia, February 2015-March 2016. PARTICIPANTS: of all participating CheckPoint families (n=1874), bone data were available for 1222 dyads (1271 children, 50% girls; 1250 parents, 86% mothers). OUTCOME MEASURES: Peripheral quantitative CT (pQCT) of the non-dominant leg scanned at the 4% (distal) and 66% (mid-calf) tibial sites. Stratec XCT 2000 software generated estimates of bone density, geometry and polar stress-strain index.Parent-child concordance were assessed using Pearson's correlation coefficients and multivariable linear regression models. Percentiles were determined using survey weights. Survey weights and methods accounted for LSAC's complex sampling, stratification and clustering within postcodes. RESULTS: Concordances were greater for the geometric pQCT parameters (periosteal circumference 0.38, 95% CI 0.33 to 0.43; endosteal circumference 0.42, 95% CI 0.37 to 0.47; total cross-sectional area 0.37, 95% CI 0.32 to 0.42) than density (cortical density 0.25, 95% CI 0.19 to 0.30). Mother-child and father-child values were similar. Relationships attenuated only slightly on adjustment for age, sex and body mass index. Percentiles and concordance are presented for the whole sample and by sex. CONCLUSIONS: There is strong parent-child concordance in bone geometry and, to a lesser extent, density even before the period of peak adolescent bone deposition. This geometrical concordance suggests that future intergenerational bone studies could consider using pQCT rather than the more commonly used dual X-ray absorptiometry (DXA).

A comparative study of quality of life, functional and bone outcomes in osteogenesis imperfecta with bisphosphonate therapy initiated in childhood or adulthood.

Bisphosphonates have been used for treatment of bone fragility disorders for over 25 years to increase bone mineral density (BMD). Anecdotally, bisphosphonate-treated Osteogenesis Imperfecta (OI) has a different trajectory to the natural history of untreated OI in terms of fracture incidence, quality of life and physical function, with minimal published evidence to support this clinical observation. This study describes functional outcomes of a cohort of adults with OI, stratified according to severity and treated with intravenous bisphosphonates as children. Reported outcomes included fracture incidence before and after puberty, mobility and BMD outcomes of this cohort. The cohort was compared to adults with OI who were never treated as children. All participants completed four questionnaires: a study specific questionnaire addressing fracture and treatment history, WHOQOL-BREF (quality of life), SF-36 (musculoskeletal function) and IPAQ (physical activity), and medical records were reviewed. Fifty-two adults with OI (80% response rate) completed the questionnaires; 33 of whom were treated with bisphosphonates in childhood. The childhood treated cohort had higher lumbar spine BMD than the adult treated cohort (z-score - 0.4 at mean age 21.3 years versus -2.1 at mean age 40.9 years; p = 0.003). Pre-pubertal fracture incidence was reduced for all severities of OI in the childhood treated cohort (less severe OI, p = 0.01; more severe OI, p < 0.001), but post-pubertal fracture incidence was higher for less severe OI (p < 0.001). In less severe OI, childhood treated individuals had higher levels of physical activity (p = 0.004) and physical functioning (p = 0.01) than adult treated individuals. Incidence of scoliosis was not different between cohorts. There were no differences in quality of life scores between the two cohorts. Improvements in BMD do not appear to influence the prevalence of scoliosis. Results suggest that treatment with bisphosphonates at an earlier age improves physical activity, particularly in less severe forms of OI but may not alter quality of life.

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents.

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

Outcomes of standardised approach to metabolic bone disease of prematurity.

AIM: To assess the current protocol of metabolic bone disease (MBD) at three Monash Health neonatal units (Melbourne, Australia). METHODS: Retrospective audit of 171 infants born at <32 weeks' gestation over 18 months. Mean gestational age was 28.6 ± 2.1 weeks, and birthweight was 1190 ± 374 g. Risk factors of MBD include intra-uterine growth retardation (n = 33, 19.3%), maternal pre-eclampsia (n = 17, 9.9%), necrotising enterocolitis (n = 9, 5.4%) and medications like methylxanthines (94.2%; mean 54.8 days), diuretics (38.6%; mean 49.2 days) and glucocorticoids (5.3%; mean 35 days). RESULTS: In total, 84.8% infants had an initial MBD screen (mean age 36.3 days), with 45% having repeated monitoring (mean age 71.9 days), and 14.2% had initial alkaline phosphatase levels >500 U/L, decreasing to 10.1% on follow-up. All infants received additional vitamin D supplementation of 400 IU/day, phosphate of 25.1% (n = 43) and calcium of 19.9% (n = 34). Fractures were identified from clinical documentation in 2.9% (n = 5) of infants. Stratifying into phosphate-treated and untreated groups revealed significant differences (P < 0.001) for gestational age and birthweight: 26.7 ± 1.7 weeks/918 ± 272 g for treated versus 29.2 ± 1.9 weeks/1283 ± 359 g for untreated. In the phosphate-treated group, improvement was seen in mean alkaline phosphatase (pre-treatment 467 ± 204 U/L and post-treatment 342 ± 221 U/L, P < 0.01) and mean phosphate levels (1.8 ± 0.4 vs. 2.2 ± 1.0 mmol/L, P < 0.01). Linear growth difference between phosphate-treated (n = 10) and untreated groups (n = 24) was insignificant at >6 months of age (P = 0.13), although this may reflect limited data. CONCLUSION: Adequate first-line supplementation with vitamin D and phosphate appeared to improve biochemical markers of MBD, but given the observational nature of this study, further longitudinal/prospective studies are required to confirm these findings.

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

Impaired bone and muscle development in young people treated with antiepileptic drugs.

OBJECTIVE: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs. METHODS: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details. RESULTS: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (Fmax total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures. SIGNIFICANCE: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes.

The effect of the ketogenic diet on the developing skeleton.

The ketogenic diet (KD) is a medically supervised, high fat, low carbohydrate and restricted protein diet which has been used successfully in patients with refractory epilepsy. Only one published report has explored its effect on the skeleton. We postulated that the KD impairs skeletal health parameters in patients on the KD. Patients commenced on the KD were enrolled in a prospective, longitudinal study, with monitoring of Dual-energy X-ray absorptiometry (DXA) derived bone parameters including bone mineral content and density (BMD). Areal BMD was converted to bone mineral apparent density (BMAD) where possible. Biochemical parameters, including Vitamin D, and bone turnover markers, including osteocalcin, were assessed. Patients were stratified for level of mobility using the gross motor functional classification system (GMFCS). 29 patients were on the KD for a minimum of 6 months (range 0.5-6.5 years, mean 2.1 years). There was a trend towards a reduction in lumbar spine (LS) BMD Z score of 0.1562 (p=0.071) per year and 20 patients (68%) had a lower BMD Z score at the end of treatment. While less mobile patients had lower baseline Z scores, the rate of bone loss on the diet was greater in the more mobile patients (0.28 SD loss per year, p=0.026). Height adjustment of DXA data was possible for 13 patients, with a mean reduction in BMAD Z score of 0.19 SD. Only two patients sustained fractures. Mean urinary calcium-creatinine ratios were elevated (0.77), but only 1 patient developed renal calculi. Children on the KD exhibited differences in skeletal development that may be related to the diet. The changes were independent of height but appear to be exaggerated in patients who are ambulant. Clinicians should be aware of potential skeletal side effects and monitor bone health during KD treatment. Longer term follow up is required to determine adult/peak bone mass and fracture risk throughout life.

Growth disorders in adolescents.

BACKGROUND: Growth is one of the fundamental processes of adolescent development. Careful history and examination, and relevant tar-geted investigations, can streamline the referral process, highlighting the important role of primary healthcare clinicians. OBJECTIVE: This article will provide a guide for clinicians to categorise growth patterns in adolescents, and recognise patients who may have a growth disorder. It will assist clinicians in considering appropriate investigations, and provide guidance for when to refer the adolescent to appropriate paediatric specialists. DISCUSSION: Causes of tall and short stature can often be distinguished on history, physical examination, and accurate pubertal staging. The height of the adolescent should always be considered in the context of their genetic potential. Physiological variants re-main the most common reason for short stature, but awareness of the features of pathological causes is critical. One of the most common presentations is maturational delay in males, and an approach to this issue is discussed.

Low vitamin D is associated with hypertension in paediatric obesity.

AIM: The aim of this paper was to investigate the relationship between circulating 25-hydroxyvitamin D (25(OH)D) and cardio-metabolic risk factors in a large cohort of obese youth attending tertiary paediatric obesity services. METHODS: We conducted a retrospective cross-sectional study. Data were retrospectively collected from all new consultations of children and adolescents attending obesity outpatient clinics between 2008 and 2011 at the two major paediatric hospitals in Melbourne, Australia. Information collected included demographics, anthropometry, blood pressure, pubertal staging, body composition and fasting serum levels of 25(OH)D, glucose, insulin, cholesterol, triglyceride, high-density lipoprotein, liver function, calcium and phosphate. RESULTS: 25(OH)D data were available in 229 patients (age 3-18 years; 116 men; mean (standard deviation) body mass index ( BMI) Z-score 2.5 (0.5) ). One hundred four (45%) participants were 25(OH)D deficient (<50 nmol/L). Lower serum 25(OH)D levels were associated with higher BMI Z-score (P-trend = 0.001), total fat mass (P-trend = 0.009), systolic (P-trend = 0.03) and diastolic blood pressures(P-trend = 0.009). In multivariable-adjusted regression analysis, 25(OH)D was significantly lower in those with elevated blood pressure after adjustment for BMI(P-trend = 0.004) or total fat mass (P-trend = 0.01). CONCLUSION: Overweight and obese youth attending specialist obesity services have a high prevalence of vitamin D deficiency. In this population, lower levels of vitamin D were seen in those with greater adiposity, and independent of this, in those who had higher blood pressure.

Bone density assessment in a tertiary paediatric centre over 13 years: Referral patterns and limitations.

AIM: This study aims to examine the referral practices for the Royal Children's Hospital (RCH) bone density service over the past 13 years and to demonstrate referral patterns and possible limitations to accessing paediatric bone densitometry. METHODS: All patients attending the RCH Healthy Bones Unit for bone densitometry from 1 July 1999 to 30 June 2012, aged under 18 years of age, were included. Densitometry results were downloaded directly from the Hologic scanner into an Excel document. However, the referring unit and indication for referral were collected manually from either the referral card or the hospital's scanned medical records system. RESULTS: A total of 5767 bone densitometry scans were performed over the study period on 3004 patients. The majority of referrals were made by the Endocrinology department, followed by Adolescent Medicine, Gastroenterology and Neurology. Relatively few referrals were made by general paediatrics. The most common indication for bone density test overall was eating disorders, followed by steroid use, osteogenesis imperfecta and other collagen disorders and inflammatory bowel disease. The lowest lumbar spine z-scores by indication were for cerebral palsy and other causes of immobility. CONCLUSIONS: Multiple childhood diseases predispose to low bone density; however, paediatric bone densitometry is still underutilised and not appropriately supported by subsidies.