Browsing by Author "Fukumoto, Seiji"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    12589 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Adult X-linked Hypophosphatemia
    (Oxford University Press, 2024-10-05) Ali, Dalal S.; Mirza, Reza; Alsarraf, Farah; Hussein, Salma; Appelman-Dijkstra, Natasha; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Brandi, Maria Luisa; Chaussain, Catherine; Cohen-Solal, Martine; Crowley, Rachel K.; Dandurand, Karel; Florenzano, Pablo F.; Fukumoto, Seiji; Gagnon, Claudia; Goodyer, Paul; Grasemann, Corinna; Imel, Erik Allen; De Beur, Suzanne Marie Jan; Lewiecki, E. Michael; Morgante, Emmett; Ward, Leanne; Aziz Khan, Aliya; Guyatt, Gordon; Medicine, School of Medicine
    Objective: Our objective was to examine the highest certainty evidence addressing the management of X-linked hypophosphatemia in adults, aiming to inform treatment recommendations. Eligibility criteria: We searched Embase, MEDLINE, Web of Science, and Cochrane from inception to March 2023 and included RCTs and observational studies enrolling individuals ≥ 18 years diagnosed with XLH on clinical grounds or with a confirmed pathogenic variant in PHEX. Manuscripts evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment were selected. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB). GRADE was used to assess certainty of evidence. Results: After removing duplicates from 7,043 citations, we assessed 254 full texts. Of those, one RCT proved eligible. The RCT of burosumab versus no treatment was at low RoB with certainty of evidence on individual outcomes ranging from high to very low. Burosumab probably improves pain inferred from fracture and pseudofracture healing (moderate certainty); however, burosumab probably has little or no impact on direct pain measures (moderate certainty). While burosumab may reduce the need for parathyroidectomy, indicated by lowered PTH levels (low certainty), it has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may also increase dental abscesses (low certainty). No formal comparisons of burosumab and conventional therapy exist; therefore, our low certainty evidence inferences regarding burosumab versus conventional therapy were based on indirect evidence from comparisons of burosumab versus no treatment and from conventional therapy versus no treatment. Observational studies proved at high RoB providing very low certainty of evidence regarding the impact of conventional therapy versus no treatment. This evidence pertained to the reduction in the risk of parathyroidectomy, as well as the reduction in the burden of symptoms caused by chronic hypophosphatemia. Conclusion: Burosumab when compared to no treatment may improve pain through fracture healing and may reduce the need for parathyroidectomy, but it could also increase the risk of dental abscess. However, when using direct measures of pain and function, burosumab demonstrated probably little or no impact on pain and stiffness, little or no impact on fatigue, and may have had little to no impact on mobility. Very low certainty exists regarding conventional therapy versus no treatment in adults. Overall, our review highlights the need for more data to better understand the long-term impact of burosumab and conventional therapy on patient-important outcomes.
  • Thumbnail Image
    Item
    12605 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Children X-linked Hypophosphatemia
    (Oxford University Press, 2024-10-05) Ali, Dalal S.; Mirza, Reza; Hussein, Salma; Alsarraf, Farah; Alexander, R. Todd; AbuAlrob, Hajar; Brandi, Maria Luisa; Carpenter, Thomas O.; Dandurand, Karel; Filler, Guido; Florenzano, Pablo F.; Fukumoto, Seiji; Grasemann, Corinna; Imel, Erik A.; De Beur, Suzanne Marie Jan; Morgante, Emmett; Ward, Leanne M.; Aziz Khan, Aliya; Guyatt, Gordon; Medicine, School of Medicine
    Objective: We sought to examine the highest certainty evidence on managing X-linked hypophosphatemia (XLH) in children, aiming to inform treatment recommendations of XLH international guidelines. Data Sources: We searched Embase, MEDLINE, Web of Science, and Cochrane Central from inception to March 2023. We also reviewed reference lists of eligible studies and pertinent review articles. Study eligibility criteria: Eligible studies included randomized controlled trials (RCTs) and observational studies enrolling individuals younger than 18 years old with XLH diagnosed on clinical grounds or with a confirmed pathogenic variant in PHEX. Articles were selected according to specific criteria evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB) in eligible articles. We employed the GRADE methodology to evaluate the certainty of the evidence. Results: After removing duplicates from 7,043 citations, we screened 4,114 records and assessed 254 full texts, of which in the systematic review (SR) addressing burosumab one RCT and one post-Hoc study proved eligible. Being open-label design, the RoB was high, with certainty of evidence on individual outcomes ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity, and improves physical health quality of life (QoL) (moderate certainty). It might also increase height and possibly improve the burden of symptoms related to chronic hypophosphatemia (low certainty). Conversely, burosumab probably increases Treatment-Emergent adverse events after the first administration (moderate certainty), and it may increase dental abscesses (low certainty). In the second SR, one observational study assessing conventional therapy versus no treatment was at high RoB providing very low certainty of evidence regarding the impact of conventional therapy compared to no treatment on final height. Conclusion: Our review indicates that burosumab likely offers benefits in preventing lower limb deformity and improving physical health QoL, while potentially increasing height and improving the burden of symptoms related to chronic hypophosphatemia (low certainty). However, it may also increase adverse events, including dental abscesses. Additionally, our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height in children. These findings highlight the need for further research to better understand the long-term impact of conventional therapy and burosumab in children.
  • Thumbnail Image
    Item
    Advancing patient evidence in XLH (APEX): rationale and design of a real-world XLH global data unification program
    (Frontiers Media, 2025-04-07) Brandi, Maria Luisa; Carpenter, Thomas O.; Fukumoto, Seiji; Haffner, Dieter; Imel, Erik A.; Kanematsu, Masanori; McCullough, Keith P.; Ozono, Keiichi; Medicine, School of Medicine
    X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder caused by pathogenic variants in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, resulting in excess fibroblast growth factor 23 (FGF23) and consequent renal phosphate wasting. Chronic hypophosphatemia leads to deficits of the musculoskeletal system affecting bone, muscle, joint, and dental health. XLH treatments include oral phosphate and active vitamin D-which are associated with a burdensome dosing regimen, gastrointestinal disturbances, hyperparathyroidism, and nephrocalcinosis-or burosumab, a fully human anti-FGF23 antibody. Randomized clinical trials (RCTs) demonstrated burosumab to be well tolerated and efficacious in improving serum phosphate, rickets, bone turnover, and patient-reported outcomes. However, there are limited data on the natural history of XLH or real-world comparisons of the safety, effectiveness, and long-term outcomes of XLH treatments. Advancing Patient Evidence in XLH (APEX) is a global data unification project aiming to describe the burden and lifelong progression of XLH, collect real-world data on treatment effectiveness and safety, and investigate regional differences in treatment outcomes. Participants from three observational, noninterventional, retrospective and prospective, multicenter, longitudinal (10-year) studies of patients with XLH will be included: XLH Disease Monitoring Program (NCT03651505), International XLH Registry (NCT03193476), and SUNFLOWER (NCT03745521). Data collected in the Americas, Europe, Israel, Japan, and South Korea will be processed to unify identical and similar data elements. Data unification will be an iterative process with a clinical and programming review, ensuring validity and accuracy. In this observational study, unified data involving approximately 2000 pediatric and adult participants with XLH will be analyzed to address research questions in an exploratory manner. Long-term observational studies and patient registries provide opportunities to generate real-world data and address knowledge gaps in rare diseases. APEX aims to improve clinical decision-making and practice by bridging evidence gaps that cannot be addressed by RCTs or regional registries.
  • Thumbnail Image
    Item
    Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia
    (Wiley, 2023) Jan de Beur, Suzanne M.; Minisola, Salvatore; Xia, Wei-bo; Abrahamsen, Bo; Body, Jean-Jacques; Brandi, Maria Luisa; Clifton-Bligh, Roderick; Collins, Michael; Florenzano, Pablo; Houillier, Pascal; Imanishi, Yasuo; Imel, Erik A.; Khan, Aliya A.; Zillikens, M. Carola; Fukumoto, Seiji; Medicine, School of Medicine
    Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.
  • Thumbnail Image
    Item
    Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Adult Patients With X-Linked Hypophosphatemia
    (Oxford University Press, 2025) Ali, Dalal S.; Mirza, Reza D.; Alsarraf, Farah; Hussein, Salma; Alrob, Hajar Abu; Appelman-Dijkstra, Natasha M.; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Brandi, Maria Luisa; Carpenter, Thomas O.; Chaussain, Catherine; Cohen-Solal, Martine; Crowley, Rachel K.; Dandurand, Karel; Florenzano, Pablo; Fukumoto, Seiji; Gagnon, Claudia; Goodyer, Paul; Grasemann, Corinna; Imel, Erik A.; Jan de Beur, Suzanne M.; Lehman, Anna; Lewiecki, E. Michael; Morgante, Emmett; Ward, Leanne M.; Khan, Aliya A.; Guyatt, Gordon; Medicine, School of Medicine
    Context: Understanding the effects of burosumab compared to conventional therapy or no treatment on patient-important outcomes in adults with X-linked hypophosphatemia (XLH) is essential to guide evidence-based treatment recommendations. Objective: To examine the highest certainty evidence addressing the management of XLH in adults to inform treatment recommendations. Methods: We searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals aged 18+ with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to no treatment or conventional therapy (phosphate and active vitamin D) and conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty. Results: We screened 4114 records, after removing duplicates, and assessed 254 full texts. One RCT and 2 observational studies were eligible. The RCT of burosumab vs no treatment had low RoB. Burosumab probably improves pain from fracture/pseudofracture healing (moderate certainty) but has little or no impact on direct pain measures (moderate certainty). Burosumab may reduce the need for parathyroidectomy (low certainty) but has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may increase dental abscess risk (low certainty). Indirect evidence comparing burosumab to conventional therapy provided low certainty regarding burosumab vs conventional therapy. Two observational studies on conventional therapy vs no treatment had high RoB and very low certainty regarding the impact of conventional therapy on patient-important outcomes. Conclusion: No formal comparisons between burosumab and conventional therapy in adults exist. Evidence for conventional therapy vs no treatment is very uncertain. Our review highlights the need for more data on the long-term effects of burosumab and conventional therapy on patient-important outcomes in adult patients with XLH.
  • Thumbnail Image
    Item
    Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Pediatric Patients With X-Linked Hypophosphatemia
    (Oxford University Press, 2025) Ali, Dalal S.; Mirza, Reza D.; Hussein, Salma; Alsarraf, Farah; Alexander, R. Todd; Alrob, Hajar Abu; Appelman-Dijkstra, Natasha M.; Biosse-Duplan, Martin; Brandi, Maria Luisa; Carpenter, Thomas O.; Chaussain, Catherine; Dandurand, Karel; Filler, Guido; Florenzano, Pablo; Fukumoto, Seiji; Grasemann, Corinna; Imel, Erik A.; Jan de Beur, Suzanne M.; Morgante, Emmett; Ward, Leanne M.; Khan, Aliya A.; Guyatt, Gordon; Medicine, School of Medicine
    Objective: To examine the evidence addressing the management of X-linked hypophosphatemia (XLH) in children to inform treatment recommendations. Methods: We searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals younger than 18 years with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to either no treatment or conventional therapy (phosphate and active vitamin D) or evaluating conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty. Results: We screened 4114 records and assessed 254 full texts. One RCT and one post hoc study proved eligible when comparing burosumab to conventional therapy or no treatment. The open-label RCT was at high RoB, with certainty of evidence ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity and improves physical health quality of life (QoL) (moderate certainty). Burosumab may increase height and enhance the burden of symptoms related to chronic hypophosphatemia (low certainty). Burosumab probably increases treatment-emergent adverse events (moderate certainty) and may increase dental abscesses (low certainty). One observational study assessing conventional therapy vs no treatment was at high RoB, providing very low certainty evidence regarding the impact of conventional therapy on final height. Conclusion: Our review indicates that burosumab likely provides benefits to children by preventing lower limb deformity and improving physical health QoL while potentially increasing height. However, burosumab may also increase adverse events. Our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height. Further research is required to understand the long-term effect of medical therapy in children.