Outcome of adult patients with X‐linked hypophosphatemia caused by <i>PHEX</i> gene mutations

Chesher, Douglas; Oddy, Michael; Darbar, Ulpee; Sayal, Parag; Casey, Adrian; Ryan, Aidan; Sechi, Annalisa; Simister, Charlotte; Waters, Aoife; Wedatilake, Yehani; Lachmann, Robin; Murphy, Elaine

doi:10.1007/s10545-018-0147-6

Cited by 110 publications

(106 citation statements)

References 43 publications

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“…Symptoms often do not appear responsive to vitamin D and phosphate therapy and are reported to progress as patients age. Many of these symptoms may be due to progressive degenerative joint disease secondary to the effects of childhood rickets, since adults with XLH often require early joint replacement and other orthopaedic procedures [14]. Other symptoms, however, could be due to the continuing effects of elevated FGF23.…”

Section: Treatment and Alleviaɵonmentioning

confidence: 99%

Exploring the burden of X-linked hypophosphatemia: a European multi-country qualitative study

Lachmann

Williams

et al. 2020

Qual Life Res

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Introduction X-linked hypophosphatemia (XLH) is a rare, lifelong, progressive disease characterised by renal phosphate wasting and abnormal bone mineralisation. Symptoms begin in early childhood, with the development of rickets and related skeletal deformities and reduced growth, progressing to long-term complications, including pseudofractures and fractures, as well as pain, stiffness and fatigue. The present study was designed to explore the patient experience of pain, stiffness and fatigue and the psychosocial impact of XLH in detail. Methods A cross-sectional qualitative study was conducted in the United Kingdom (18), Finland (6), France (4), Germany (1) and Luxembourg (1) with XLH patients aged 26 and over. Interview discussion guides were developed in consultation with clinical experts and patient associations. Data were analysed thematically. Results Participants (N = 30) described pain, stiffness and fatigue as frequently experienced symptoms with a significant impact on physical functioning and activities of daily living (ADLs). Some also described the symptoms as impacting their mood/mental health, relationships, social life and leisure activities. Participants described how common symptoms could interact or aggravate other symptoms. Symptoms had often worsened over time, and for many, were associated with concern about the future. Most participants were worried or felt guilty about having children with XLH. The findings confirmed and extended the existing model of the burden of XLH. Conclusion The present study is the first to provide an in-depth analysis of pain, stiffness and fatigue, their impact and the interrelatedness of these symptoms among adults with XLH. The study also described the psychosocial impact of XLH as a hereditary, lifelong progressive disease.

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Section: Treatment and Alleviaɵonmentioning

confidence: 99%

Exploring the burden of X-linked hypophosphatemia: a European multi-country qualitative study

Lachmann

Williams

et al. 2020

Qual Life Res

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“…Low serum phosphorus levels result in rickets and osteomalacia, the hallmarks of XLH in children and adults, respectively. Osteomalacia is associated with poor bone quality that results in pseudofractures, fractures, impaired fracture healing, and bone and joint pain …”

Section: Introductionmentioning

confidence: 99%

“…Osteomalacia is associated with poor bone quality that results in pseudofractures, fractures, impaired fracture healing, and bone and joint pain. (3)(4)(5) Since the 1980s, conventional therapy for XLH has consisted of multiple daily doses of oral phosphate and one or more doses of an active vitamin D metabolite. (1,2) Although this therapy has been the standard of care for children with XLH, there is no consensus regarding its use in adults.…”

Section: Introductionmentioning

confidence: 99%

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

Insogna

Rauch

Kamenický

et al. 2019

Journal of Bone and Mineral Research

121

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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 < 0.0001). All subjects had one or more treatment‐emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure‐related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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“…Loss of function mutations of PHEX or DMP-1 lead to dramatic increases in FGF23 release from bone with increased circulating levels of FGF23 [20,21]) impaired 1,25(OH) 2 D 3 formation, renal phosphate wasting, hypophosphatemia, and impairment of bone mineralization [21][22][23][24], as amplified below.…”

Section: Cellular Mechanisms Regulating Fgf23 Releasementioning

confidence: 95%

“…The excessive increase of plasma FGF23 concentrations, compromized 1,25(OH) 2 D 3 formation and renal phosphate wasting in patients carrying loss of function mutations of PHEX [20,22]) interferes with bone mineralization leading to several clinical disorders including limb deformity, short stature, arthritis, enthesopathy, hearing impairment, optic atrophy and nephrocalcinosis [21][22][23][24]. Loss of function mutations of DMP-1 lead to rickets/ osteomalacia later during childhood or in adulthood [23].…”

Section: Clinical Significance Of Fgf23 Excessmentioning

confidence: 99%

Phosphate Homeostasis, Inflammation and the Regulation of FGF-23

Läng

Leibrock

Pandyra

et al. 2018

Kidney Blood Press Res

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Fibroblast growth factor 23 (FGF23) is released primarily from osteoblasts/osteocytes in bone. In cooperation with the transmembrane protein Klotho, FGF23 is a powerful inhibitor of 1α 25OH Vitamin D Hydroxylase (Cyp27b1) and thus of the formation of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). As 1,25(OH)₂D₃ up-regulates intestinal calcium and phosphate absorption, the downregulation of 1,25(OH)₂D₃ synthesis counteracts phosphate excess and tissue calcification. FGF23 also directly inhibits renal phosphate reabsorption. Other actions of FGF23 include triggering of cardiac hypertrophy. FGF23 formation and/or release are stimulated by 1,25(OH)₂D₃, phosphate excess, Ca²⁺, PTH, leptin, catecholamines, mineralocorticoids, volume depletion, lithium, high fat diet, iron deficiency, TNFα and TGFß2. The stimulating effect of 1,25(OH)₂D₃ on FGF23 expression is dependent on RAC1/PAK1 induced actin-polymerisation. Intracellular signaling involved in the stimulation of FGF23 release also includes increases in the cytosolic Ca²⁺ concentration ([Ca²⁺]i) following intracellular Ca²⁺ release and store-operated Ca²⁺ entry (SOCE). SOCE is accomplished by the Ca²⁺ release-activated calcium channel protein 1 (Orai1) and its stimulator stromal interaction molecule 1 (STIM1). Expression of Orai1, SOCE and FGF23-formation are up-regulated by the proinflammatory transcription factor NFκB. The present brief review describes the cellular mechanisms involved in FGF23 regulation and its sensitivity to both phosphate metabolism and inflammation. The case is made that up-regulation of FGF23 by inflammatory mediators and signaling may amplify inflammation by inhibiting formation of the anti-inflammatory 1,25(OH)₂D₃.

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Outcome of adult patients with X‐linked hypophosphatemia caused by PHEX gene mutations

Cited by 110 publications

References 43 publications

Exploring the burden of X-linked hypophosphatemia: a European multi-country qualitative study

Exploring the burden of X-linked hypophosphatemia: a European multi-country qualitative study

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

Phosphate Homeostasis, Inflammation and the Regulation of FGF-23

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