Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period.

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

Effect of Calcium and Vitamin D Supplementation (Dairy vs. Pharmacological) on Bone Health of Underprivileged Indian Children and Youth with Type-1 Diabetes: A Randomized Controlled Trial.

BACKGROUND: Bone health is affected by chronic childhood disorders including type-1 diabetes mellitus (T1DM). We conducted this randomized controlled trial with the objective of investigating the effect of 1-year supplementation of vitamin-D with milk or with pharmacological calcium on bone mass accrual in underprivileged Indian children and youth with T1DM. METHODS: 5 to 23year old (n = 203) underprivileged children and youth with T1DM were allocated to one of three groups: Milk (group A-received 200 ml milk + 1000 international unit (IU) vitamin-D3/day), Calcium supplement (group B-received 500 mg of calcium carbonate + 1000 IU of vitamin-D3/day) or standard of care/control (group C). Anthropometry, clinical details, biochemistry, diet (3-day 24-h recall), physical activity (questionnaires adapted for Indian children) and bone health parameters (using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography- DXA and pQCT respectively) were evaluated at enrolment and end of 12 month intervention. RESULTS: Total body less head(TBLH) bone mineral content (BMC(g)) and bone mineral density (BMD(gm/cm2)) were significantly higher at end of study in girls in both supplemented groups (TBLHBMC-A-1011.8 ±â€¯307.8, B-983.2 ±â€¯352.9, C-792.8 ±â€¯346.8. TBLHBMD-A-± 0.2, B-0.8 ±â€¯0.2, C-0.6 ±â€¯0.2, p < 0.05). Z score of lumbar spine bone mineral apparent density of supplemented participants of both sexes was significantly higher than controls (Boys- A-0.7 ±â€¯1.1, B-0.6 ±â€¯1.4, C- -0.7 ±â€¯1.1; Girls- A-1.1 ±â€¯1.1, B-0.9 ±â€¯3.4, C- -1.7 ±â€¯1.3, p < 0.05). A significantly higher percentage increase was found in cortical thickness in girls in both supplemented groups (A-17.9 ±â€¯28.6, B-15.3 ±â€¯16.5, C-7.6 ±â€¯26.2); the differences remained after adjusting for confounders. CONCLUSION: Supplementation with milk or pharmacological calcium (+vitaminD3) improved bone outcomes-particularly geometry in children with T1DM with more pronounced effect in girls. Pharmacological calcium may be more cost effective in optimising bone health in T1DM in resource limited settings.

Effect of Yoga or Physical Exercise on Muscle Function in Rural Indian Children: A Randomized Controlled Trial.

BACKGROUND: Synergistic effects of yoga or physical exercise (PE) along with protein supplementation on children's muscle function in rural India have not been studied. Hence, we aimed to study the effect of yoga and PE along with protein supplementation on muscle function in healthy 6- to 11-year-old rural Indian children post 6 months of intervention. METHODS: A randomized controlled trial on 232 children, recruited into 3 groups, each receiving 1 protein-rich ladoo (148 kcal, 7 g protein/40 g ladoo-an Indian sweet snack) daily and performing (1) yoga (n = 78) for 30 minutes 5 times per week, (2) PE (n = 76) for 30 minutes 5 times per week, or (3) control group (n = 78) no additional exercise. Maximum power, maximum voluntary force (Fmax), and grip strength (GS) were measured. Data were analyzed using paired t tests and a 2-way mixed analysis of variance with post hoc Bonferroni adjustment. RESULTS: GS, maximum power, and Fmax within yoga group increased significantly (P < .05) from baseline to endline. GS and Fmax increased significantly within PE group postintervention (P < .001). In controls, GS increased (P < .05) at endline. No significant effect of the intervention was observed on the change in maximum power (P > .05) postintervention. The 2 exercise groups showed significant increase in Fmax compared with the control group (P < .05). Similarly, increase in GS was significantly higher in both the exercise groups compared with the control group (P < .05). No significant difference was observed in change in muscle function between the 2 exercise groups (P > .05). CONCLUSIONS: Structured physical activity along with protein supplementation resulted in improved muscle function in children. Yoga and PE showed a comparable impact on muscle force.

Reducing Metabolic Bone Disease Burden in Intestinal Failure Children on Home Parenteral Nutrition.

Objective: To determine the prevalence of secondary hyperparathyroidism in a cohort of pediatric patients receiving home parenteral nutrition. Methods: For a service review, a population-based cohort of 37 pediatric intestinal failure patients receiving long-term parenteral nutrition that underwent serial biochemical monitoring during a study period of approximately 4 years were examined. Following the production of an algorithm, a follow-up audit was carried out (n = 33) after approximately 6 months. Results: Of the 37 patients examined in the initial service review, 22 (59%) were found to have an elevated parathyroid hormone (PTH) during the period of monitoring and 5 (14%) had a persistently elevated PTH. In the follow-up audit following the implementation of an algorithm, the number with elevated PTH reduced to 6 (18%) and no patients had persistently high levels. Conclusion: Elevated PTH is a common biochemical finding in pediatric intestinal failure patients receiving home parenteral nutrition and its presence should alert clinicians to the need to optimize nutritional parameters such as calcium to phosphate molar ratio and vitamin D status; failure to do so may increase the future burden of metabolic bone disease in such patients. We propose that an algorithm may help in this endeavor.

Characterisation of parathyroid hormone concentration in extremely preterm or very low birthweight infants in routine clinical screening for metabolic bone disease: A service evaluation cohort study.

AIM: To characterise parathyroid hormone (PTH) concentrations in infants at high risk for metabolic bone disease, in order to assist clinical decisions around the use of PTH for screening. METHODS: Infants born under 28 weeks' postmenstrual age or with birthweight under 1.5 kg in a tertiary neonatal unit in the UK were included. Clinical guidance was to assess PTH concentration in the first 3 weeks after birth. Clinical information was extracted from prospective records. RESULTS: Sixty-four infants had mean birth gestation of 26 weeks and birthweight of 882 g. Median PTH (sent on median day 18 of life) was 9.2 pmol/L (interquartile range 5.3-17 pmol/L). Sixty-seven per cent of infants had a PTH greater than 7 pmol/L. For 22% of the infants, raised PTH was not accompanied by abnormal phosphate or alkaline phosphatase. Eighty-nine per cent of infants tested were insufficient or deficient for 25-hydroxyvitamin D. CONCLUSIONS: Universal screening highlights the high frequency of high PTH in this high-risk population, implying a need for calcium supplementation. A considerable number of infants would not be identified as showing potential signs of metabolic bone disease if the assessment excludes the use of PTH. The high level of 25-hydroxyvitamin D deficiency may be a confounder.

Burosumab vs Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis by Dose Level.

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.

Refractory Rickets.

Nutritional rickets, caused by vitamin D and/or calcium deficiency is by far the most common cause of rickets. In resource-limited settings, it is therefore not uncommon to treat rickets with vitamin D and calcium. If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis. Chronic low serum phosphate is the pathological hallmark of all forms of rickets as its low concentration in extracellular space leads to the failure of apoptosis of hypertrophic chondrocytes leading to defective mineralisation of the growth plate. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) control serum phosphate concentration by facilitating the excretion of phosphate in the urine through their action on the proximal renal tubules. An increase in PTH, as seen in nutritional rickets and genetic disorders of vitamin D-dependent rickets (VDDRs), leads to chronic low serum phosphate, causing rickets. Genetic conditions leading to an increase in FGF23 concentration cause chronic low serum phosphate concentration and rickets. Genetic conditions and syndromes associated with proximal renal tubulopathies can also lead to chronic low serum phosphate concentration by excess phosphate leak in urine, causing rickets.In this review, authors discuss an approach to the differential diagnosis and management of refractory rickets.

Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3.

OBJECTIVES: To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). STUDY DESIGN: A formal neurodevelopmental assessment was performed in children diagnosed with FHH3. The Vineland Adaptive Behavior Scales, which is a standardized parent report assessment tool for adaptive behavior, was used to assess communication, social skills, and motor function and to generate a composite score. RESULTS: Six patients were diagnosed with hypercalcemia between 0.1 and 8 years of age. All had neurodevelopmental abnormalities in childhood consisting of either global developmental delay, motor delay, expressive speech disturbances, learning difficulties, hyperactivity, or autism spectrum disorder. Four out of the 6 probands had a composite Vineland Adaptive Behavior Scales SDS of < -2.0, indicating adaptive malfunctioning. Significant deficits were observed in the domains of communication (mean SDS: -2.0, P < .01), social skills (mean SDS: -1.3, P < .05), and motor skills (mean SDS: 2.6, P < .05). Individuals were equally affected across domains, with no clear genotype-phenotype correlation. All family members affected with FHH3 also described evidence of neurodevelopmental dysfunction, including mild-to-moderate learning difficulties, dyslexia, and hyperactivity. CONCLUSION: Neurodevelopmental abnormalities appear to be a highly penetrant and common feature of FHH3, and early detection is warranted to provide appropriate educational support. This case series also supports consideration of serum calcium measurement as part of the diagnostic work-up in any child presenting with unexplained neurodevelopmental abnormalities.

Approach to nutritional rickets.

Rickets is the disease of a growing skeleton and results from impaired apoptosis of hypertrophic chondrocytes and mineralization of the growth plate. Nutritionally induced rickets, secondary to vitamin D and/or calcium deficiency, remains a major global problem. In this review, we discuss pathogenesis, clinical signs, investigation and management of nutritional rickets.

Phosphate Homeostasis and Disorders of Phosphate metabolism.

Phosphate is indispensable for human life and evolutionary changes over several millions of years have established tightly regulated mechanisms to ensure phosphate homeostasis. In this process, calcium and phosphate metabolism have come to be intricately linked together. Three hormones (PTH, FGF23 and Calcitriol) maintain the fine balance of calcium and phosphate metabolism through their actions at three sites (the gut, the kidneys and the skeleton). Disorders that disrupt this balance can have serious clinical consequences. Acute changes in serum phosphate levels can result in life threatening complications like respiratory failure and cardiac arrythmias. Chronic hypophosphataemia predominantly affects the musculoskeletal system and presents as impaired linear growth, rickets, osteomalacia and dental problems. Hyperphosphataemia is very common in the setting of chronic kidney disease and can be difficult to manage. A thorough understanding of calcium and phosphate homeostasis is essential to diagnose and treat conditions associated with hypo and hyperphosphataemia. In this review, we will discuss the calcium and phosphate metabolism, aetiologies and management of hypo and hyperphosphataemia.

Vitamin D status and determinants in Indian children and adolescents: a multicentre study.

Studies performed on Indian children to assess vitamin-D status have been on small sample sizes, limited to specific geographical locations and used non-standard methods to measure 25(OH)D3. This multicentre study assessed 25(OH)D3 concentrations from dried blood spots (DBS) in 5-18-year-old Indian children and adolescents using a standardized protocol and identified factors contributing towards vitamin D deficiency. Cross-sectional, observational school-based study was conducted by multi-stage stratified random sampling. A city and nearby village were selected from 6 Indian states covering wide geographical areas. Demography, anthropometry, body-composition, dietary-intakes and DBS samples were collected. 25(OH)D3 was assessed from DBS using Liquid chromatography with tandem-mass spectrometry. Vitamin-D status was assessed in 2500 children; with additional data collected on a subset (n = 669) to assess predictors. Mean vitamin-D concentration was 45.8 ± 23.9 nmol/L, 36.8% of subjects had sufficient vitamin-D (> 50 nmol/L); rural subjects and boys had higher concentrations (p < 0.05). On regression analysis, younger age, female-gender, overweight and urban residence significantly contributed to deficiency. More than half the Indian children/adolescents were vitamin-D deficient or insufficient. Our study reinforces vitamin-D deficiency as a major public health problem and the need for supplementation, food fortification and educating the population as initiatives required to improve sufficiency status.

Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia.

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.

Determinants of muscle power and force as assessed by Jumping Mechanography in rural Indian children.

OBJECTIVES: To: 1. Assess muscle function (MF) of rural Indian children (6-11y, n=232), using Jumping Mechanography (JM) and hand dynamometer, 2. Investigate gender differences, 3. Identify determinants of MF. METHODS: Data on anthropometry, muscle mass%, diet, physical activity, sunlight exposure, MF (maximum relative power Pmax/mass, maximum relative force Fmax/BW by JM; relative grip strength (RGS) by hand dynamometer) were collected. Pearson's correlation and hierarchical linear regression was performed. RESULTS: Pmax/mass, Fmax/BW and RGS of the group were 31.7±5.0W/kg, 3.0±0.3 and 0.4±0.1 (mean±SD), respectively. The Pmax/mass Z-score was -1.1±0.9 and Fmax/BW Z-score was -0.9±1 (mean±SD) which was significantly lower than the machine reference data (p<0.05). Positive association of muscle mass% and protein intake was observed with all MF parameters and moderate+vigorous physical activity with Fmax/BW (p<0.05). Determinants of MF identified through regression for Pmax/mass were age (ß=1.83,95% CI=0.973 - 2.686), muscle mass% (ß=0.244,95% CI=0.131-0.358) and protein intake (ß=3.211,95% CI=1.597-4.825) and for Fmax/BW was protein intake (ß=0.130,95% CI=0.023-0.237) (p<0.05). Male gender was a positive predictor of having higher Pmax/mass (ß=1.707,95% CI=0.040-3.373) (p<0.05). CONCLUSION: MF was lower than in western counterparts. To optimize MF of rural Indian children, focus should be on improving muscle mass, ensuring adequate dietary protein, and increasing physical activity, especially in girls.

The skeletal muscle phenotype of children with Neurofibromatosis Type 1 - A clinical perspective.

Neurofibromatosis type 1 (NF1) can affect multiple systems in the body. An under recognised phenotype is one of muscle weakness. Clinical studies using dynamometry and jumping mechanography have demonstrated that children with NF1 are more likely to have reduced muscle force and power. Many children with NF1 are unable to undertake physical activities to the same level as their peers, and report leg pains on physical activity and aching hands on writing. Children and adolescents with NF1 reporting symptoms of muscle weakness should have a focused assessment to exclude alternative causes of muscle weakness. Assessments of muscle strength and fine motor skills by physiotherapists and occupational therapists can provide objective evidence of muscle function and deficits, allowing supporting systems in education and at home to be implemented. In the absence of an evidence base for management of NF1-related muscle weakness, we recommend muscle-strengthening exercises and generic strategies for pain and fatigue management. Currently, trials are underway involving whole-body vibration therapy and carnitine supplementation as potential future management options.

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.

PURPOSE: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH. METHODS: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab. RESULTS: Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ±â€…0.1 (least squares mean ±â€…SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity. MAIN CONCLUSIONS: In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab. CLINICALTRIALS.GOV: NCT02163577.

Impact of Adolescent Pregnancy on Bone Density in Underprivileged Pre-Menopausal Indian Women.

High prevalence (31.5%) of adolescent pregnancies (AP) have been reported in India. Reports suggest that pregnancy during adolescence may have deleterious effects on peak bone mass. Very few studies have described the long-term effects of a history of AP on bone mass. The objective of this study was to compare bone mineral density (BMD) and bone geometry of premenopausal women with first childbirth during adolescence (i.e., before age of 19 years) or after 20 years. A cross-sectional study was conducted in 242 women (age 28.0-54.5 years) from Pune, India (November, 2015 to November, 2017). Women were divided into 2-groups: Group-1: women-who had 1st-pregnancy and childbirth before 19 years of age (AP n = 131) and Group-2: women-who had 1st pregnancy after 20 years of age (non-AP n = 111). Demographic data, anthropometric measurements, and biochemical tests were performed using standard protocols. Physical activity and nutrient intakes were recorded using validated questionnaires. Areal BMD and bone geometry were measured using Dual-Energy-Absorptiometry-DXA (Lunar-iDXA, GE Healthcare) and peripheral-quantitative-computed-tomography-pQCT (XCT2000, Stratec Inc.). Mean age of the study group was 37 ± 4.6 years; in women from group-1 mean age at first delivery was 16.9 ± 1.6 years as against 22.6 ± 3.1 years in group-2. Both groups were similar in body mass index and socioeconomic status. pQCT measured radial diaphyseal cortical thickness (1.97 ± 0.3 mm vs 1.88 ± 0.3 mm resp., p = 0.016, periosteal circumference (38.0 ± 3.6 mm vs 36.7 ± 2.5 mm, resp. p = 0.016), total bone area (114.3 ± 24.8 mm2 vs 108.7 ± 14.7 mm2 resp. p = 0.026) and stress-strain index (SSI = 217 ± 75 vs 201 ± 40 mm3 resp. p = 0.042) were significantly higher in group-1 than group-2. After adjusting for anthropometric and lifestyle parameters, pQCT measured cortical thickness (1.98 ± 0.03 mm in group-1, 1.87 ± 0.03 mm group-2, p = 0.01, mean ± SE) and iDXA derived aBMD at forearm were still significantly higher (0.599 ± 0.006 g/cm3 vs 0.580 ± 0.006 g/cm3, p = 0.023) in Group-1. Our data suggest that women with a history of adolescent pregnancy had better bone geometry and higher aBMD at radius in later years. We speculate that early exposure to pregnancy resulted in higher aBMD at the radius and induced changes at radial diaphysis with bones becoming thicker and wider among these women.

Normal Mid-Gestation Fetal Ultrasonography Cannot Reliably Exclude Severe Perinatal Hypophosphatasia.

INTRODUCTION: Hypophosphatasia is a systemic bone disease characterized by inhibition of bone mineralization due to mutations in the ALPL gene that results in a deficiency of tissue nonspecific alkaline phosphatase. The perinatal form is the most severe. In the past, this form was lethal, although human recombinant enzyme replacement therapy has now been developed and licensed, which improves survival. Perinatal hypophosphatasia is usually suggested on antenatal ultrasonography with undermineralization of the long bones, skull, and thoracic cavity. In the UK, antenatal ultrasonography for fetal anomalies is conducted at mid-gestation (i.e., 18-21 weeks gestational age), and if normal, no further routine scans are performed. Usually, this would identify abnormalities in bone mineralization suggestive of perinatal hypophosphatasia. CASES: We describe 2 cases of perinatal hypophosphatasia where mid-gestation ultrasonography was normal. In the first case, where a previous pregnancy had been terminated for perinatal hypophosphatasia, third trimester ultrasonography revealed skeletal features of hypophosphatasia. In the second case, the diagnosis of perinatal hypophosphatasia was made only immediately after birth. CONCLUSION: We conclude that serial antenatal ultrasonography or antenatal genetic testing should be considered in all pregnancies with a positive family history of hypophosphatasia, as mid-gestation ultrasonography cannot reliably exclude perinatal hypophosphatasia. This is especially important given that effective enzyme replacement therapy is now available.

Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial.

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 ±â€…3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ±â€…0.79 to -1.49 ±â€…1.05 on ZA, compared with -2.38 ±â€…0.90 to -2.27 ±â€…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.

Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia.

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.