Dataset Information

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.

ABSTRACT: In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0?mg/kg administered every 4?weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2?years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48?weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, -54%, osteoid thickness, -32%, osteoid surface/bone surface, -26%, [median] mineralization lag time, -83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3?mg/dL, a 50% increase from 2.2?mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p?

SUBMITTER: Insogna KL

PROVIDER: S-EPMC6916280 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.

Insogna Karl L KL Rauch Frank F Kamenický Peter P Ito Nobuaki N Kubota Takuo T Nakamura Akie A Zhang Lin L Mealiffe Matt M San Martin Javier J Portale Anthony A AA

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20191001 12

In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating th ...[more]

PMID: 31369697

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Project description:X-linked hypophosphatemia (XLH) or vitamin D-resistant rickets (MIM#307800), is a monogenic disorder with X-linked inheritance. It is caused by mutations present in the Phosphate Regulating Endopeptidase Homolog X-Linked (PHEX) gene responsible for the degradation of the bone-derived hormone fibroblast growth factor 23 (FGF23) into inactive fragments, but the entire mechanism is currently unclear. The inactivation of the gene prevents the degradation of FGF23, causing increased levels of FGF23, which leads to decreased tubular reabsorbtion of phosphorus. Clinical aspects are growth delay, limb deformities, bone pain, osteomalacia, dental anomalies, and enthesopathy. Laboratory evaluation shows hypophosphatemia, elevated alkaline phosphatase (ALP), and normal serum calcium levels, whereas parathormone (PTH) may be normal or increased and FGF23 greatly increased. Conventional treatment consists of administration of oral phosphate and calcitriol. Treatment with Burosumab, a monoclonal antibody that binds to FGF23, reducing its activity, was approved in 2018.MethodsWe describe a case of two siblings, a girl and a boy, diagnosed with XLH, monitored by the Genetic Department of the County Emergency Clinical Hospital since 2019. The clinical picture is suggestive for XLH, both siblings exhibiting short stature, lower limb curvature, bone pain, marked walking weakness, and fatigue. Radiological aspects showed marked deformity of the lower limbs: genu varum in the girl, genu varum and valgum in the boy. Laboratory investigations showed hypophosphathemia, hyperphosphaturia, elevated ALP, normal PTH, and highly increased FGF23 in both. DNA analysis performed on the two siblings revealed a nonsense mutation in exone 5 of the PHEX gene: NM_000444.6(PHEX):c.565C > T (p.Gln189Ter).ResultsAt the age of 13½ on 7 June 2021, the two children started treatment with Burosumab in therapeutic doses and were monitored clinically and biochemically at regular intervals according to the protocol established by the Endocrinology Commission of the Romanian Health Ministry.ConclusionsThe first results of the Burosumab treatment in the two siblings are extremely encouraging and suggest a favorable long-term evolution under this treatment.

Dataset Information

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.

Publications

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.

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