Impact of X-linked hypophosphatemic rickets/osteomalacia on health and quality of life: baseline data from the SUNFLOWER longitudinal, observational cohort study.

The SUNFLOWER study was initiated in Japan and South Korea to clarify the course of X-linked hypophosphatemic rickets/osteomalacia (XLH); delineate its physical, mental, and financial burdens; and collect information on treatment. Here, we report cross-sectional data at the time of patient enrollment to better understand the real-world management and complications in patients with XLH and examine the effect of XLH on quality of life (QOL). This is an ongoing, longitudinal, observational cohort study of patients with a diagnosis of XLH. Data from 147 patients (118 in Japan and 29 in South Korea) were evaluated. In total, 77 children (mean age, 9.7 yr; 67.5% female) and 70 adults (mean age, 37.6 yr; 65.7% female) were enrolled. PHEX gene mutations were confirmed in 46/77 (59.7%) children and 37/70 (52.9%) adults. Most patients in both age groups were receiving a combination of phosphate and active vitamin D at baseline. The mean height Z-score was -2.21 among adults (male: -2.34; female: -2.14). The mean Rickets Severity Score in children was 1.62. Whereas children appeared to have low pain levels (mean revised faces pain scale score, 1.3), adults reported mild-to-moderate pain (mean Brief Pain Inventory pain severity, 2.02). Mean QOL in children (assessed using the 10-item short-form health survey for children) was low, with a score below normative level for physical functioning. In adults, results from the Western Ontario and McMaster Universities osteoarthritis index indicated the presence of pain, stiffness, and decreased physical function. The respective mean total days/year of work/school non-attendance due to symptoms/complications and management of XLH were 0.7 and 3.0 among adults, and 6.4 and 6.1 among children. Our findings reconfirmed a relationship between disease and QOL in patients with XLH. We anticipate that these data will be important in enabling clinicians to understand the daily reality of patients with XLH.

Recovery from rituximab-associated persistent hypogammaglobulinaemia in children with nephrotic syndrome.

BACKGROUND AND HYPOTHESIS: There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS). METHODS: A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined. RESULTS: The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio, 0.28; 95% CI, 0.09-0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children). CONCLUSIONS: A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections.

Persistent growth-promoting effects of vosoritide in children with achondroplasia are accompanied by improvements in physical and social aspects of health-related quality of life.

PURPOSE: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia. METHODS: Participants received vosoritide (15 µg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766). RESULTS: The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the QoLISSY physical score (5.99 [19.41], caregiver-reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 (22.64), respectively). Changes were greatest in participants with ≥1 SD increase in height Z-score (physical: 11.36 [19.51], caregiver-reported [n=38]; 8.48 [21.83], self-reported [n=28]) (social: 5.84 [15.45] and 9.79 [22.80], respectively). To determine how domain scores may change with age in untreated persons, models were produced using observational/untreated-person data. A 1-year increase in age was associated with a change of 0.16 (SE, 0.55) and 0.16 (0.50), for caregiver-reported physical and social domain scores, respectively. Self-reported scores changed by 1.45 (0.71) and 1.92 (0.77), respectively. CONCLUSION: These data suggest that after 3 years of treatment vosoritide demonstrates a positive effect on physical and social functioning among children with achondroplasia, particularly in children with a more pronounced change in height Z-score.

Burosumab treatment of X-linked hypophosphatemia patients: interim analysis of the SUNFLOWER longitudinal, observational cohort study.

X-linked hypophosphatemia (XLH) is a genetic disease that results in excessive FGF23, chronic hypophosphatemia, and musculoskeletal abnormalities, with affected patients experiencing symptoms such as bone pain, bone deformity, fracture, and pseudofracture. Burosumab is a fully human monoclonal antibody that binds to FGF23, improving lowered serum 1,25(OH)2D and phosphate levels in patients with XLH. There are insufficient data on the use of burosumab, its safety, and the outcomes of treated patients in a real-world setting. The SUNFLOWER (Study of longitUdinal observatioN For patients with X-Linked hypOphosphatemic rickets/osteomalacia in collaboration With Asian partnERs) study is an ongoing longitudinal, observational cohort study of patients with XLH in Japan and South Korea. Enrollment occurred between April 2018 and December 2020. This interim analysis compared the background characteristics of patients who received burosumab with those who did not, and assessed improvements in biomarkers, physical and motor function, health-related quality-of-life (HRQOL) and other patient-reported outcome (PRO) measures, as well as the safety of burosumab treatment in 143 Japanese patients from 15 institutions over 6 mo. The patients had a median [interquartile range] age of 17.5 [11.0, 38.8] yr and 98 (68.5%) were female. Among patients aged <18 and ≥18 yr, 40/73 (54.8%) and 25/70 (35.7%) received burosumab, respectively. More patients aged ≥18 who received burosumab had bone pain at baseline vs those not treated with burosumab (6/25, 24.0% vs 2/45, 4.4%, p=.021). Patients treated with burosumab had improved serum phosphate and 1,25(OH)2D levels; moreover, rickets severity and HRQOL/PRO measures, such as pain, appeared to improve over 6 mo of burosumab treatment, and no new safety concerns were identified. This study identified trends in the background characteristics of patients with XLH who receive burosumab in real-world clinical practice. Furthermore, the results support the use of burosumab therapy in real-world settings.

Promising horizons in achondroplasia along with the development of new drugs.

Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.

Clinical outcomes and medical management of achondroplasia in Japanese children: A retrospective medical record review of clinical data.

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Association of trabecular bone score and bone mineral apparent density with the severity of bone fragility in children and adolescents with osteogenesis imperfecta: A cross-sectional study.

Osteogenesis imperfecta (OI) is a hereditary skeletal disease characterized by bone fragility. Areal bone mineral density (BMD), evaluated by dual-energy X-ray absorptiometry (DXA), is used to assess bone brittleness. The height-adjusted BMD Z-score (BMDHAZ) is calculated in children and adolescents with OI to reduce the confounding factor of short stature. However, even with the BMDHAZ, severity evaluation in children and adolescents with OI is challenging because certain abnormalities in bone quality cannot be accurately assessed by BMD analysis. The trabecular bone scores (TBS) and bone mineral apparent density (BMAD), which represent the structural integrity of bone and bone-size-associated BMD, respectively, are associated with fracture risk. Recently, age- and sex-specific reference ranges have been reported, enabling the calculation of Z-scores for children. To evaluate which density measurements show the highest correlation with fracture risk, we analyzed the associations between the Z-scores of TBS, BMAD, and BMDHAZ, fracture rate, and genetic variants. We retrospectively reviewed 42 participants with OI aged 5 to 20 years who underwent DXA. COL1A1/2 pathogenic variants were detected in 41 of the 42 participants. In participants with nonsense and frameshift variants (n = 17) resulting in haploinsufficiency and mild phenotype, the TBS Z-score was negatively correlated with fracture rate (FR) (r = -0.50, p = 0.042). In participants with glycine substitution (n = 9) causing the severe phenotype, the BMAD Z-scores were negatively correlated with FR (r = -0.74, p = 0.022). No correlation between the BMDHAZ and FR was observed in both groups. These findings suggest that the TBS and BMAD are useful in assessing children and adolescents with OI with specific genetic variants.

A case of hyperphosphatemic familial tumoral calcinosis due to maternal uniparental disomy of a GALNT3 variant.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, inherited autosomal recessive disorder caused by fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) gene variants. Here, we report the case of a Japanese boy who presented with a mass in his left elbow at the age of three. Laboratory test results of the patient revealed normocalcemia (10.3 mg/dL) and hyperphosphatemia (8.7 mg/dL); however, despite hyperphosphatemia, serum intact FGF23 level was low, renal tubular reabsorption of phosphate (TRP) level was inappropriately increased, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) level was inappropriately normal. Genetic analysis revealed maternal uniparental disomy (UPD) of chromosome 2, which included a novel GALNT3 variant (c.1780-1G>C). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of GALNT3 mRNA confirmed that this variant resulted in the destruction of exon 11. We resected the mass when the patient was five years old, owing to its gradual enlargement. No relapse or new pathological lesions were observed four years after tumor resection. This is the first case report of a Japanese patient with HFTC associated with a novel GALNT3 variant, as well as the first case of HFTC caused by maternal UPD of chromosome 2 that includes the GALNT3 variant.

A family with brachydactyly mental retardation syndrome with a missense variant in HDAC4.

Brachydactyly mental retardation syndrome (BDMR) or chromosome 2q37 deletion syndrome is a genetic disorder caused by 2q37 deletion or haploinsufficiency of histone deacetylase 4 (HDAC4). The HDAC4 gene is responsible for major BDMR phenotypes. The symptoms of BDMR include mild-to-moderate intellectual disability, seizures, autism spectrum disorder, short stature, obesity, and facial dysmorphism. Here, we report a family (n = 5) with BDMR who had a missense variant of HDAC4. Four affected individuals [5-yr-old girl (index case); 15- and 3-yr-old siblings; and father] had mild intellectual disability, three of the four affected individuals had short stature and mild cardiac anomalies, and two of the four affected individuals had hypothyroidism. Whole-exome sequencing and analyses of the index case and her family revealed an allelic variant in the HDAC4 gene (NM_001378414.1:c.2204G>A:p. Arg735Gln). A healthy family member (mother) did not have the missense variant. To our knowledge, this is the first report of a missense variation in HDAC4 that is associated with BDMR.

A patient with pachydermoperiostosis harboring SLCO2A1 variants with a history of differentiating from acromegaly.

Pachydermoperiostosis (PDP) is a rare hereditary disease characterized by digital clubbing, pachydermia, and periostosis. We describe a Japanese male patient with PDP who was differentially diagnosed with acromegaly by identification of compound heterozygous variants in SLCO2A1. Recent studies have reported various clinical manifestations, as well as skeletal and dermal features, in patients with PDP. Genetic testing provided not only PDP diagnosis and differentiation from acromegaly, but also information about possible complications and comorbidities throughout life.

Assessment of body fat mass, anthropometric measurement and cardiometabolic risk in children and adolescents with achondroplasia and hypochondroplasia.

Achondroplasia is a rare skeletal dysplasia characterized by rhizomelic short stature, whose prevalence is about 1 per 25,000 births. For some patients with achondroplasia, excess body weight is one of the major concerns due to an impaired linear growth. Epidemiological studies revealed a premature onset of cardiovascular or cerebrovascular events in achondroplasia. An association between obesity and cardiometabolic risk factors related to cardiovascular events remains unknown in patients with achondroplasia/hypochondroplasia. This cross-sectional study investigated anthropometric measurements, body compositions and cardiometabolic risk factors in pediatric patients with achondroplasia/hypochondroplasia. Thirty-two patients with achondroplasia and ten with hypochondroplasia aged between 1.9 and 18.7 years were enrolled in this study. Half of the participants presented at least one cardiometabolic abnormality. Elevated systolic blood pressure was the most common abnormality. None of the participants developed metabolic syndrome or type 2 diabetes mellitus. Body mass index-standard deviation score and hip/height ratio were strongly correlated with percent body fat assessed by dual energy X-ray absorptiometry although no significant association was found between anthropometric measurements or body fat mass and any cardiometabolic risk factors. No significant difference in body fat mass, as well as body mass index-standard deviation score and hip/height, was found between cardiometabolically normal group and cardiometabolically abnormal groups. These results suggest that not only weight gain and hip/height changes should be monitored but also individual cardiometabolic risk factors should be evaluated to avoid cardiometabolic events in the healthcare management of pediatric patients with achondroplasia/hypochondroplasia.

Self-Administration of Burosumab in Children and Adults with X-Linked Hypophosphataemia in Two Open-Label, Single-Arm Clinical Studies.

INTRODUCTION: X-linked hypophosphataemia (XLH) is a rare, genetic renal phosphate-wasting disease, resulting from excess fibroblast growth factor 23 (FGF23) activity, which has a progressive and profound impact on patients throughout life. The monoclonal anti-FGF23 antibody, burosumab, is a subcutaneous injection indicated for the treatment of XLH in children and adults. Originally, burosumab was approved to be administered by a healthcare professional (HCP), but the option of self-administration would enable patient independence and easier access to treatment. Two open-label, single-arm clinical trials, conducted in Japan and Korea, have assessed the safety and efficacy of self-administration of burosumab in both children and adults with XLH. METHODS: In KRN23-003 (n = 15 children aged 1-12 years) and KRN23-004 (n = 5 children aged 3-13 years, n = 4 adults aged 21-65 years), children initially received 0.8 mg/kg of burosumab every 2 weeks and adults initially received 1.0 mg/kg of burosumab every 4 weeks. Self-administration was permitted from Week 4, and patients or carers were provided with training to inject correctly. RESULTS: In both trials, burosumab had an acceptable safety profile with mainly mild-to-moderate adverse events. Following self-administration, no patients reported serious treatment-emergent adverse events ≥ grade 3, injection-site reactions or hypersensitivity reactions related to burosumab. Serum phosphate and active vitamin D levels increased from baseline in children and adults. CONCLUSIONS: These results indicated that the efficacy and safety of burosumab when administered either by a carer or patient are similar to that when administered by an HCP and show that self-administration is a viable option for patients with XLH. TRIAL REGISTRATION NUMBERS: NCT03233126 and NCT04308096.

Prevalence of Pseudohypoparathyroidism and Nonsurgical Hypoparathyroidism in Japan in 2017: A Nationwide Survey.

BACKGROUND: Pseudohypoparathyroidism (PHP) and nonsurgical hypoparathyroidism (NS-HypoPT) are rare diseases with hypocalcemia, hyperphosphatemia, and high and low parathyroid hormone levels, respectively. In Japan, over 20 years have passed since the last survey on these diseases. We carried out a nationwide cross-sectional survey to estimate the prevalence of these diseases in 2018. METHODS: We conducted a nationwide mail-based survey targeting hospitals in 2018. From a total of 13,156 departments throughout Japan, including internal medicine, pediatrics, neurology, and psychiatry, 3,501 (27%) departments were selected using a stratified random sampling method. We asked each included department to report the number of patients with PHP and NS-HypoPT in 2017. RESULTS: The overall survey response rate was 52.0% (1,807 departments). The estimated number of patients with PHP and NS-HypoPT was 1,484 (95% confidence interval [CI], 1,143-1,825) and 2,304 (95% CI, 1,189-3,419), respectively; the prevalence per 100,000 population was 1.2 and 1.8, respectively. CONCLUSION: In this study, we generated estimates of the national prevalence of PHP and NS-HypoPT in Japan during 2017, which were found to be higher than those previously reported.

Pathogenic variants of the GNAS gene introduce an abnormal amino acid sequence in the ß6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families.

Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of GNAS, which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of GNAS (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the ß6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP.

Phosphate promotes osteogenic differentiation through non-canonical Wnt signaling pathway in human mesenchymal stem cells.

BACKGROUND: Phosphate is indispensable in osteogenesis and mineralization. However, mechanisms by which phosphate enhances osteogenic differentiation are not fully understood. In this study, we studied the effect of phosphate on osteogenic differentiation as well as signaling pathways induced by phosphate in the process. METHOD: Induced human bone marrow-derived mesenchymal stem cells differentiation into osteoblasts by the change of media containing ß-glycerophosphate (GP), 1 mM inorganic phosphate, or 3 mM inorganic phosphate (Pi). The differentiation of osteoblasts was verified by the expression of osteoblast differentiation markers and calcium deposition. RNA sequencing was performed to assess transcriptome in the early stage of osteogenic differentiation. RESULTS: Osteogenic differentiation and mineralization were promoted in the 3 mM Pi group compared to those in the GP and 1 mM Pi groups on day 7 of culture. RNA sequencing revealed that the gene expressions involved in osteogenesis and the components in the Wnt signaling pathway was increased in 3 mM Pi group compared with those in the GP on day 7. Analysis with qPCR and Western blot suggested upregulation of components in the non-canonical Wnt signaling pathway, including WNT5b and phosphorylated-c-Jun in the 3 mM Pi group on day 7. WNT11 mRNA expression was increased in the 2 induction groups on day 7. Inhibition of WNT5b by siRNA experiment attenuated the components in non-canonical Wnt signaling expression, including WNT5b, WNT11 and ROR2 mRNA expression and phosphorylated-c-Jun protein expression. In addition, osteogenic differentiation and mineralization were partly decreased in 3 mM Pi group on day 7 by the inhibition of WNT5b. CONCLUSION: Pi promoted osteogenic differentiation through the up-regulation of the non-canonical Wnt signaling pathway, including WNT5b, WNT11, p-c-Jun/c-Jun, in the early stage of differentiation. These findings provide a new perspective into the association of Pi and the non-canonical Wnt signaling pathway during osteogenic differentiation.

Efficacy of Burosumab in Adults with X-linked Hypophosphatemia (XLH): A Post Hoc Subgroup Analysis of a Randomized Double-Blind Placebo-Controlled Phase 3 Study.

The anti-fibroblast growth factor 23 monoclonal antibody burosumab corrects hypophosphatemia in adults with X-linked hypophosphatemia (XLH) and improves pain, stiffness, physical function, and fatigue. This post hoc subgroup analysis used data from the 24-week placebo-controlled period of a phase 3 study in 134 adults with XLH (ClinicalTrials.gov NCT02526160), to assess whether the benefits of burosumab are evident in 14 clinically relevant subgroups defined by baseline demographic and functional criteria, including sex, Brief Pain Inventory-short form (BPI-SF) Average And Worst Pain, region, race, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Stiffness, Physical Function and Pain domains and total score, use of opioid/other pain medication, active fractures/pseudo-fractures, and 6-min walk test distance. There were no statistically significant interactions between any of the subgroups and treatment arm for any endpoint. Higher proportions of subjects achieved mean serum phosphate concentration above the lower limit of normal (the primary endpoint) with burosumab than with placebo in all subgroups. For the key secondary endpoints (WOMAC Stiffness and Physical Function; BPI-SF Worst Pain) individual subgroup categories showed improvements with burosumab relative to placebo. For additional efficacy endpoints, burosumab was favored in some subgroups but differences were not significant and confidence intervals were wide. For some endpoints the treatment effect is small at 24 weeks in all subjects. This subgroup analysis shows that burosumab was largely superior to placebo across endpoints in the 14 clinically relevant subgroup variables at 24 weeks and is likely to benefit all symptomatic adults with active XLH.

Safety and Efficacy of Burosumab in Pediatric Patients With X-Linked Hypophosphatemia: A Phase 3/4 Open-Label Trial.

Objective: Burosumab, an anti-fibroblast growth factor 23 antibody, was recently approved for the treatment of X-linked hypophosphatemia (XLH).We evaluated the safety and efficacy of burosumab in pediatric XLH patients. Methods: This open-label, phase 3/4 trial of ≤ 124 weeks' duration was conducted at 4 Japanese medical centers. Fifteen children aged 1 to 12 years with XLH were included. All had previously been treated with phosphorus or vitamin D. Subcutaneous burosumab was administered every 2 weeks, starting with 0.8 mg/kg, and adjusted based on serum phosphorus levels and any safety concerns (maximum 2 mg/kg). Safety assessments included the frequency of treatment-emergent adverse events (TEAEs). Efficacy of burosumab on biochemical markers, clinical markers of rickets, motor function, and growth was also evaluated. Results: The average treatment duration was 121.7 weeks. Frequently reported TEAEs were nasopharyngitis (46.7%), dental caries (40.0%), and influenza (33.3%). At baseline, patients had low serum phosphorus concentrations (2.6 ±â€…0.3 mg/dL) and low-to-normal 1,25-dihydroxyvitamin D concentrations (24.7 ±â€…12.7 pg/mL), which increased with burosumab treatment and were maintained during the study period. Alkaline phosphatase decreased continuously. At baseline, the mean ±â€…SD total Thacher Rickets Severity Score (RSS) was 1.3 ±â€…1.2, and 4 patients (26.7%) had an RSS ≥ 2.0. Mean Radiographic Global Impression of Change and RSS tended to improve, particularly in patients with higher baseline RSS. There was a trend toward increased 6-minute walk test distance. No apparent changes in growth rate were observed. Conclusion: Burosumab has a good safety profile and is effective in pediatric patients with XLH.

Inconvenience and adaptation in Japanese adult achondroplasia and hypochondroplasia: A cross-sectional study.

The health-related quality of life is reduced in patients with achondroplasia (ACH) and hypochondroplasia (HCH); however, the detailed inconveniences in the daily living and individual adaptations have not been elucidated. This study aimed to evaluate the inconvenience and adaptation in patients with ACH/HCH. A cross-sectional study was conducted in patients with ACH/HCH aged 20 yr or older. Questionnaires were sent to 567 patients (described 86) with a medical history at the co-authors' institutions or who were registered at the patients' association with ACH in Japan. The questionnaire included a free description format for the inconveniences and adaptations in daily living; a content analysis was performed. The recorded inconveniences included 148 physical, 84 mental, and 52 social problems. Patients who underwent spine surgery had significantly more recorded physical problems than those who did not (p < 0.05). Pain and numbness were significantly higher in patients aged ≥ 50 yr (p < 0.05). The 160 and 1 adaptations were for physical and social problems, respectively. No patient adaptation was found for mental health problems. Individual adaptations by ACH/HCH patients can improve only some aspects of physical and social problems. Multilateral social support is needed to resolve patients' issues.