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Introduction: The objective of this study was to better understand the clinical profiles of children with hypophosphatasia (HPP) prior to treatment with enzyme replacement therapy (ERT). Methods: Pretreatment demographics and medical histories of ERT-treated children (aged <18 years) enrolled in the Global HPP Registry (2015–2020) were analyzed overall, by age at first HPP manifestation (<6 months vs. 6 months to 18 years), and by geographic region (USA/Canada, Europe, and Japan). Results: Data from 151 children with HPP were analyzed. Sex distribution was balanced overall (52.3% female; 47.7% male) but differed in Japan (63.0% female; 37.0% male). Prior to ERT initiation, common manifestations were skeletal (67.5%) and extraskeletal, with the foremost types being muscular (48.3%), constitutional/metabolic (47.0%), and neurologic (39.7%). A high proportion of children who first presented at <6 months of age (perinatal/infantile period) had a history of bone deformity (59.3%) and respiratory failure (38.3%), while those aged 6 months to 18 years at first manifestation had a predominance of early loss of primary teeth (62.3%) and gross motor delay (41.0%). Those from Japan were reported to have a younger median age overall, the highest proportion of skeletal manifestations (80.4%) and growth impairment, while European data reported the highest proportion of muscular manifestations (70.7%). In the USA/Canada, skeletal and muscular manifestations were reported at the same frequency (57.4%). Conclusion: Prior to ERT, skeletal and extraskeletal manifestations were commonly reported in children with HPP, with differences by age at first HPP manifestation and geographical region. Comprehensive assessments of children with HPP are warranted prior to ERT initiation. [ABSTRACT FROM AUTHOR]

Background: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. Methods: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. Results: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60–632 m) at baseline (n = 31) to 484 m at Month 12 (range 240–739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from − 0.72 (95% CI: − 1.23, − 0.21; n = 38) to − 1.13 (95% CI: − 1.76, − 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. Conclusions: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. Registration: NCT02306720; EUPAS13514. [ABSTRACT FROM AUTHOR]

Context Impairments in musculoskeletal and mental health are common in adults with Hypophosphatasia (HPP). Restricted phosphorus intake has been suggested to positively affect symptoms in HPP, but there is a lack of interventional evidence. Objective This work aimed to evaluate the effect of a phosphorus-restricted, calcium-adjusted diet on musculoskeletal and mental health in HPP. Methods A prospective, noncontrolled, single-center interventional study (NuSTEPS II) was conducted among outpatients at the Osteology Department, University of Wuerzburg, Germany. A total of 26 adults with an established HPP diagnosis received a standardized diet with a defined daily intake of phosphorus (1160-1240 mg/d) and calcium (870-930 mg/d) over 8 weeks. Main outcome measures were functional testing and patient-reported outcome measures. Results At 8 weeks, significant improvements were observed in usual gait speed (P =.028) and the chair-rise test (P =.019), while no significant changes were seen in the 6-minute walk test (P =.468) and the timed up-and-go test (P =.230). Pain was not significantly reduced according to the visual analog scale (VAS) (P =.061), pain subscale of the 36-Item Short-Form Health Survey (SF-36) (P =.346), and Pain Disability Index (P =.686). Further, there was a significant improvement in the SF-36 vitality subscale (P =.022) while all other subscales as well as the Lower Extremity Functional Scale (P =.670) and the Fatigue Assessment Scale (P =.392) did not change significantly. Adjustments of mineral intake were not associated with relevant alterations regarding the intake of energy and energy-supplying nutrients or body composition. Conclusion Adjusting phosphorus and calcium intake may positively affect individual symptoms in adults with HPP, but overall clinical effectiveness regarding major issues like pain and endurance appears limited. [ABSTRACT FROM AUTHOR]

Context: X-linked hypophosphatemia (XLH) is a rare genetic disease, characterized by renal phosphate wasting and complex musculoskeletal manifestations including decreased physical performance. Objective: To characterize muscular deficits in patients with XLH and investigate phosphate stores in muscles. Methods: Case--control study (Muscle fatigability in X-linked Hypophosphatemia [MuXLiH]) with a 1-time assessment at the German Aerospace Center (DLR), Cologne, from May to December 2019, including patients with XLH cared for at the Osteology Department, University of Wuerzburg. Thirteen patients with XLH and 13 age/sex/body weight--matched controls aged 18-65 years were included. The main outcome measure was 31P-magnetic resonance spectroscopy (31P-MRS)--based assessment of phosphate metabolites in the soleus muscle at rest. Further analyses included magnetic resonance imaging--based muscle volume measurement, laboratory testing, isokinetic maximum voluntary contraction (MVC), fatigue testing, and jumping mechanography. Results: By means of 31P-MRS, no significant differences were observed between XLH and controls regarding phosphate metabolites except for a slightly increased phosphocreatine to inorganic phosphate (PCr/Pi) ratio (XLH: 13.44 ± 3.22, control: 11.01 ± 2.62, P = .023). Quadriceps muscle volume was reduced in XLH (XLH: 812.1 ± 309.0 mL, control: 1391.1 ± 306.2 mv, P < .001). No significant differences were observed regarding isokinetic maximum torque (MVC) adjusted to quadriceps muscle volume. Jumping peak power and jump height were significantly reduced in XLH vs controls (both P < .001). Conclusion: The content of phosphoric compounds within the musculature of patients with XLH was not observed to be different from controls. Volume-adjusted muscle strength and fatiguability were not different either. Reduced physical performance in patients with XLH may result from long-term adaptation to reduced physical activity due to skeletal impairment. [ABSTRACT FROM AUTHOR]

BACKGROUND. Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme. METHODS. In this phase IIA open-label, single-center, intra-patient, dose -escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti -sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up. RESULTS. Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment -associated adverse events were mild and transient. CONCLUSION. BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP. TRIAL REGISTRATION. Clinicaltrials.gov NCT01406977. FUNDING. Novartis Institutes for BioMedical Research, Basel, Switzerland., Introduction Hypophosphatasia (HPP) is a rare genetic metabolic disorder (OMIM 171760) caused by mutations in the alkaline phosphatase (ALP) gene ALPL (1p36.12), which encodes tissue-nonspecific ALP (TNSALP) enzyme and results [...]