Browsing by Author "Ward, Leanne"
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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 MedicineObjective: 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.Item Musculoskeletal Features in Adults With X-linked Hypophosphatemia: An Analysis of Clinical Trial and Survey Data(Endocrine Society, 2022) Javaid, Muhammad Kassim; Ward, Leanne; Pinedo-Villanueva, Rafael; Rylands, Angela J.; Williams, Angela; Insogna, Karl; Imel, Erik A.; Medicine, School of MedicineContext: Patients with X-linked hypophosphatemia (XLH) experience multiple musculoskeletal manifestations throughout adulthood. Objective: To describe the burden of musculoskeletal features and associated surgeries across the lifespan of adults with XLH. Methods: Three groups of adults were analyzed: subjects of a clinical trial, participants in an online survey, and a subgroup of the online survey participants considered comparable to the clinical trial subjects (according to Brief Pain Inventory worst pain scores of ≥ 4). In each group, the adults were categorized by age: 18-29, 30-39, 40-49, 50-59, and ≥ 60 years. Rates of 5 prespecified musculoskeletal features and associated surgeries were investigated across these age bands for the 3 groups. Results: Data from 336 adults were analyzed. In all 3 groups, 43% to 47% had a history of fracture, with the proportions increasing with age. The overall prevalence of osteoarthritis was > 50% in all 3 groups, with a rate of 23% to 37% in the 18- to 29-year-old group, and increasing with age. Similar patterns were observed for osteophytes and enthesopathy. Hip and knee arthroplasty was reported even in adults in their 30s. Spinal stenosis was present at a low prevalence, increasing with age. The proportion of adults with ≥ 2 musculoskeletal features was 59.1%, 55.0%, and 61.3% in the clinical trial group, survey group, and survey pain subgroup, respectively. Conclusion: This analysis confirmed high rates of multiple musculoskeletal features beginning as early as age 20 years among adults with XLH and gradually accumulating with age.Item Nephrocalcinosis and kidney function in children and adults with X-linked hypophosphatemia: baseline results from a large longitudinal study(Oxford University Press, 2024) Portale, Anthony A.; Ward, Leanne; Dahir, Kathryn; Florenzano, Pablo; Ing, Steven W.; Jan de Beur, Suzanne M.; Martin, Regina M.; Meza-Martinez, Adriana I.; Paloian, Neil; Ashraf, Ambika; Dixon, Bradley P.; Khan, Aliya; Langman, Craig; Chen, Angel; Wang, Christine; Scott Roberts, Mary; Tandon, P. K.; Bedrosian, Camille; Imel, Erik A.; Medicine, School of MedicineBackground: In patients with X-linked hypophosphatemia (XLH), conventional therapy with oral phosphate salts and active vitamin D has been associated with nephrocalcinosis. However, the nature of the relationships among XLH, its treatment, nephrocalcinosis, and kidney function remain poorly understood. Methods: Renal ultrasounds were performed and glomerular filtration rates were estimated (eGFR) at baseline in burosumab-naïve patients with XLH who participated in burosumab clinical trials (NCT02181764, NCT02526160, NCT02537431, NCT02163577, NCT02750618, NCT02915705) or enrolled in the XLH Disease Monitoring Program (XLH-DMP; NCT03651505). In this cross-sectional analysis, patient, disease, and treatment characteristics were described among patients with and without nephrocalcinosis. Results: The analysis included 196 children (mean [SD] age 7.6 [4.0] yr) and 318 adults (40.3 [13.1] yr). Mean (SD) height z-score was -1.9 (1.2) for children and -2.3 (1.7) for adults. Nearly all children (97%) and adults (94%) had previously received conventional therapy. Nephrocalcinosis was detected in 22% of children and 38% of adults. In children, reduced eGFR <90 mL/min/1.73 m2 was more prevalent in those with nephrocalcinosis (25%) than in those without (11%), a finding that was not observed in adults. Children with nephrocalcinosis had lower mean values of TmP/GFR (p<.05), serum 1,25(OH)2D (p<.05), and eGFR (p<.001) and higher mean serum calcium concentrations (p<.05) than did those without nephrocalcinosis. Adults with nephrocalcinosis had lower mean serum phosphorus (p<.01) and 1,25(OH)2D (p<.05) concentrations than those without. Exploratory logistic regression analyses revealed no significant associations between the presence of nephrocalcinosis and other described patient or disease characteristics. Conclusions: Nephrocalcinosis was observed in nearly one-quarter of children and more than one-third of adults with XLH. Further study is needed to better understand the predictors and long-term consequences of nephrocalcinosis, with surveillance for nephrocalcinosis remaining important in the management of XLH.Item OR13-2 Burosumab Resulted in Greater Improvement in Rickets Than Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH)(Oxford University Press, 2019-04-15) Imel, Erik; Whyte, Michael; Munns, Craig; Portale, Anthony; Ward, Leanne; Nilsson, Ola; Simmons, Jill; Padidela, Raja; Namba, Noriyuki; Cheong, Hae Il; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; San Martin, Javier; Glorieux, Francis; Medicine, School of MedicineXLH is characterized by excess FGF23, hypophosphatemia, skeletal deformities, and growth impairment. For the last 40 years, XLH has been treated with multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab, a fully human monoclonal antibody to FGF23, has been approved by the FDA for the treatment of XLH in patients ≥1 year-old. In this Phase 3 trial (NCT02915705), 61 children with XLH (1-12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks or continue Pi/D titrated and individualized for each subject by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 despite prior treatment with Pi/D (>7-day washout before baseline). The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C). The mean ± SE daily oral phosphate dose from baseline to Week 40 was 37.8 ± 3.2 mg/kg, with >99% compliance reported based on days of dosing. Compared with Pi/D, 40 weeks of burosumab resulted in a greater LS mean ± SE increase in serum phosphorus (0.92 ± 0.08 vs 0.20 ± 0.06 mg/dL), TmP/GFR (1.19 ± 0.11 vs -0.16 ± 0.05 mg/dL), and 1,25(OH)2D (30 ± 4 vs 19 ± 4 pg/mL). At Week 40, rickets improved in both groups; RGI-C global score was significantly higher in burosumab subjects than in Pi/D subjects (LS mean ± SE: +1.9 ± 0.1 vs +0.8 ± 0.1; p<0.0001). More burosumab subjects had substantial healing (RGI-C ≥+2.0), compared with Pi/D subjects (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, p<0.0001). Improvement in the RGI-C lower limb deformity score was greater with burosumab than with Pi/D (+0.62 ± 0.12 vs +0.21 ± 0.12; p=0.02). Alkaline phosphatase decreased more with burosumab compared with Pi/D (-131 ± 13 vs 35 ± 19; p<0.0001). Consistent with decreases in rickets severity, burosumab improved growth and mobility. Standing height Z-score increased by a LS mean change (95% CI) of +0.15 (0.05, 0.25) for burosumab and +0.08 (-0.02, 0.19) for Pi/D. The 6 Minute Walk Test percent predicted distance increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Nephrocalcinosis score (range 0-4) shifted 0 in 20 Pi/D and 24 burosumab subjects; +1 in 3 Pi/D and 0 burosumab subjects; and -1 in 3 Pi/D and 2 burosumab subjects. Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reactions, were higher in the burosumab group and were mild to moderate in severity overall. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved. No subject discontinued study drug in either group. Data after 64 weeks of treatment will be available at the time of presentation. In this randomized Phase 3 trial, burosumab resulted in increases in growth and mobility, and significantly greater improvements in rickets than Pi/D in 1-12 year-old children with XLH.Item Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children(Elsevier, 2017-04) Ballesteros, Luisa F. Gonzalez; Ma, Nina S.; Gordon, Rebecca J.; Ward, Leanne; Backeljauw, Philippe; Wasserman, Halley; Weber, David R.; DiMeglio, Linda A.; Gagne, Julie; Stein, Robert; Cody, Declan; Simmons, Kimber; Zimakis, Paul; Topor, Lisa Swartz; Agrawal, Sungeeta; Calabria, Andrew; Tebben, Peter; Faircloth, Ruth; Imel, Erik A.; Casey, Linda; Carpenter, Thomas O.; Department of Pediatrics, School of MedicineObjective Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. Methods A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. Results Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. Conclusion The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.