Safety and efficacy of long term asfotase alfa treatment in childhood hypophosphatasiad'Angelo, Lauriola, Silvestrini
et alItal J Pediatr (2025) 51 (1), 86
Abstract: Hypophosphatasia (HPP) is a rare inherited disorder characterized by a deficiency of tissue-non-specific alkaline phosphatase (TNSALP) due to loss-of-function variants of the ALPL gene. HPP is characterized by an extremely variable age of onset and clinical presentation, largely depending on the type of genetic disruption. Childhood HPP commonly presents with skeletal deformities, bone fragility, precocious tooth loss, muscle weakness and sometimes neurological implications. Laboratory tests usually document low levels of alkaline phosphatase (ALP), and radiologic investigations show peculiar bone abnormalities. Treatment with human recombinant TNSALP (asfotase alpha, Strensiq®), available since 2015, is associated with a sudden improvement and a good safety profile.A previously healthy 15-month-old girl presented with progressive "genu valgus" and sudden limping. The patient was diagnosed with childhood HPP due to the presence of two ALPL variants, never described in compound heterozygosity: a missense variant c.571G > A, p.(Glu191Lys), and a frameshift deletion c.963delG; p.(Lys322Argfs*44), both classified as pathogenetic. The child was promptly treated with asfotase alpha, and good improvement was quickly obtained. Efficacy, safety, and good tolerance persisted after a long-term follow-up of 6 years.Pediatricians should consider HPP in children presenting with a suggestive clinical phenotype. Calcium-phosphorus metabolism, ALP, and vitamin B6 should always be investigated in suspected cases. Moreover, asfotase alfa represents a safe, well-tolerated, and effective drug in children with HPP.© 2025. The Author(s).
Hindlimb unloading reversibly attenuates osteogenic potential of rat skeletal stem and progenitor cells ex vivoMarkina, Andreeva, Buravkova
Cells Tissues Organs (2025)
Abstract: Prolonged space flights negatively affect skeleton. Stromal cells of mesenchymal origin play a crucial role in maintaining homeostasis and in regulating the physiological remodeling of various tissues, and this has particular significance for bone.Hindlimb unloading (HU) of rats as a ground-based model for simulation of microgravity was implemented. The functional activity of skeletal stem and progenitor cells (SSPCs) from rat femoral bones was assessed in vitro after 2 weeks of HU and after 2 weeks of subsequent recovery of load support (HU+R). To characterize the growth of the SSPCs, the number of population doublings (PD) was calculated. Histochemical detection of the activity of alkaline phosphatase (AP) - an early marker of osteo-differentiation - on day 7, and of extracellular matrix (ECM) mineralization - as a sign of late osteo-differentiation - on day 21, were carried out. Quantitative real-time PCR was performed to detect the expression of the genes encoding proteins associated with the functional activity of osteoprogenitor cells (Pparg, Runx2, Alpl, Cxcl12) and bone tissue homeostasis (Mmp9, Spp1, RANKL, OPG, Ibsp, BMP10, Sost).After HU, a decrease in AP activity and a significant attenuation of extracellular matrix mineralization were detected. There was also significant downregulation of the genes those for bone matrix proteins (RANKL, OPG, Ibsp), and of the master-genes controlling osteo- and adipo-differentiation (Runx2, Alpl), as well as of Mmp9, encoding a regulatory molecule of bone matrix remodeling. By contrast, sclerostin (Sost) was upregulated. After HU+R, the PD, an AP activity and the level of extracellular matrix mineralization were restored.HU leads to inhibition of the osteoplastic function of SSPCs. The presented data are significant for the elucidation of microgravity-induced mechanisms of bone impairment and for the development of countermeasures for astronauts as well as for osteo-deficient patients after prolonged immobilization.S. Karger AG, Basel.
Current Perspectives on Additive Manufacturing and Titanium Surface Nanotopography in Bone Formationda Costa Valente, Uehara, Lisboa Batalha
et alJ Biomed Mater Res B Appl Biomater (2025) 113 (3), e35554
Abstract: This study aimed to assess the impact of manufacturing methods (conventional and additive manufacturing) and surface treatments (polished and nanotopographic) on the physicochemical properties of Ti6Al4V alloy and their correlation with osteoblast cellular behavior. The evaluated groups were Machined Discs (MD), Machined Discs with Treatment (MD-WT), Additive-manufactured Discs (AD), and Additive-manufactured Discs with Treatment (AD-WT). Surface analyses included SEM, AFM, surface roughness, EDS, XRD, surface free energy, and zeta potential. MC3T3-E1 cells were cultured for biological assessments, including cell morphology, viability, gene expression, alkaline phosphatase activity, and mineralization. ANOVA and Holm-Sidak tests were applied (p < 0.05). MD exhibited grooved topography, AD had partially fused spherical particles, while MD-WT and AD-WT showed patterns from chemical treatment (H3PO4 + NaOH). EDS identified additional ions in MD-WT and AD-WT. XRD patterns indicated crystal lattice orientation differences. MD-WT and AD-WT displayed higher surface free energy than MD and AD (p < 0.05). AD had greater roughness (Sa 6.98 μm, p < 0.05). Biological analyses revealed higher cell viability for MD and AD (p < 0.001), higher ALP activity in MD, and lower in AD-WT. Gene expression varied, with MD showing higher Alpl, Ibsp, and Bglap (p < 0.001), and AD-WT showing higher Runx2 (p < 0.001). Mineralized matrix behavior was similar for MD, AD, and MD-WT (p > 0.05). MD and AD surfaces demonstrated superior osteogenic differentiation potential, while AD exhibited greater roughness, lower surface free energy, higher cell viability, and osteoblastic differentiation potential.© 2025 Wiley Periodicals LLC.
Long-Term Outcomes of Early Enzyme Replacement Therapy With Asfotase Alfa in Perinatal Benign Hypophosphatasia: Amelioration of Bone Deformities in a Young ChildTerayama, Kobayashi, Suemitsu
et alCureus (2025) 17 (2), e78473
Abstract: Hypophosphatasia (HPP) is a congenital skeletal dysplasia. Enzyme replacement therapy (ERT) improves survival and bone mineralization of patients with perinatal severe HPP. However, there are few reports of ERT in patients with perinatal benign HPP, and its long-term efficacy remains unclear. Herein, we report the case of a boy with perinatal benign HPP who was initiated on early ERT with asfotase alpha. The patient was suspected of having HPP because of shortened limbs and deformed long bones on fetal 3D-CT. He was diagnosed with HPP based on clinical manifestations, low serum alkaline phosphatase levels, and ALPL gene variants. At the age of two years and three months, he had muscle weakness and motor developmental delay requiring support to walk, and ERT was initiated. His muscle strength improved immediately, and he could walk independently two months after starting ERT. Shortening and bowed limbs improved, and his body height increased from -3.48 SD (at the age of two years and three months) to -1.71 SD (at the age of nine years and eight months) after starting ERT. Hence, early ERT effectively improves motor development, bone deformity, and short stature in patients with perinatal benign HPP.Copyright © 2025, Terayama et al.
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