Browsing by Subject "Osteomalacia"
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Item A 61-year-old woman with osteomalacia and a thoracic spine lesion(Wiley, 2010-03) Marshall, Ann E.; Martin, Sarah E.; Agaram, Narasimhan P.; Chen, Jey-Hsin; Horn, Eric M.; Douglas-Akinwande, Annette C.; Hattab, Eyas M.; Pathology and Laboratory Medicine, School of MedicinePhosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) is a rare, largely benign, mesenchymal neoplasm almost invariably associated with oncogenic osteomalacia. It is generally found in the soft tissue and bone of the extremities. We report a case of a 61-year-old female with long-standing osteomalacia who was found to have PMT-MCT of the thoracic spine. There have been very few previously reported cases of PMT involving the spinal vertebrae and neuropathologists should be aware of this lesion. Recognition of PMT-MCT is critical for optimal patient care since complete surgical resection without additional therapy is curative.Item Burosumab for the Treatment of Tumor‐Induced Osteomalacia(Wiley, 2021-04) Jan de Beur, Suzanne M.; Miller, Paul D.; Weber, Thomas J.; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Rauch, Frank; Luca, Diana; Cimms, Tricia; Scott Roberts, Mary; Martin, Javier San; Carpenter, Thomas O.; Medicine, School of MedicineTumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia.Item Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period(Springer, 2019-09-01) Portale, Anthony A.; Carpenter, Thomas O.; Brandi, Maria Luisa; Briot, Karine; Cheong, Hae II; Cohen-Solal, Martine; Crowley, Rachel; Jan De Beur, Suzanne; Eastell, Richard; Imanishi, Yasuo; Imel, Erik A.; Ing, Steven; Ito, Nobuaki; Javaid, Muhammad; Kamenicky, Peter; Keen, Richard; Kubota, Takuo; Lachmann, Robin; Perwad, Farzana; Pitukcheewanont, Pisit; Ralston, Stuart H.; Takeuchi, Yasuhiro; Tanaka, Hiroyuki; Weber, Thomas J.; Yoo, Han-Wook; Zhang, Lin; Theodore-Oklota, Christina; Mealiffe, Matt; San Martin, Javier; Insogna, Karl; Medicine, School of MedicineBurosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.Item FGF23 Synthesis and Activity(Springer, 2019-03) Noonan, Megan L.; White, Kenneth E.; Medical and Molecular Genetics, School of MedicinePurpose of review: The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH)2 vitamin D (1,25D). Novel regulators of FGF23 were recently identified, and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23. Recent findings: The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations. Summary: Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance will be reviewed.Item Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-linked hypophosphatemia (XLH)(Wiley, 2022) Sarafrazi, Soodabeh; Daugherty, Sean C.; Miller, Nicole; Boada, Patrick; Carpenter, Thomas O.; Chunn, Lauren; Dill, Kariena; Econs, Michael J.; Eisenbeis, Scott; Imel, Erik A.; Johnson, Britt; Kiel, Mark J.; Krolczyk, Stan; Ramesan, Prameela; Truty, Rebecca; Sabbagh, Yves; Medicine, School of MedicineX-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemia, is caused by disrupting variants in the PHEX gene, located on the X chromosome. XLH is inherited in an X-linked pattern with complete penetrance observed for both males and females. Patients experience lifelong symptoms resulting from chronic hypophosphatemia, including impaired bone mineralization, skeletal deformities, growth retardation, and diminished quality of life. This chronic condition requires life-long management with disease-specific therapies, which can improve patient outcomes especially when initiated early in life. To centralize and disseminate PHEX variant information, we have established a new PHEX gene locus-specific database, PHEX LSDB. As of April 30, 2021, 870 unique PHEX variants, compiled from an older database of PHEX variants, a comprehensive literature search, a sponsored genetic testing program, and XLH clinical trials, are represented in the PHEX LSDB. This resource is publicly available on an interactive, searchable website (https://www.rarediseasegenes.com/), which includes a table of variants and associated data, graphical/tabular outputs of genotype-phenotype analyses, and an online submission form for reporting new PHEX variants. The database will be updated regularly with new variants submitted on the website, identified in the published literature, or shared from genetic testing programs.Item OR13-1 Burosumab Improves the Biochemical, Skeletal, and Clinical Symptoms of Tumor-Induced Osteomalacia Syndrome(Oxford University Press, 2019-04-15) Jan De Beur, Suzanne; Miller, Paul; Weber, Thomas; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Luca, Diana; Theodore-Oklota, Christina; Lampl, Kathy; San Martin, Javier; Carpenter, Thomas; Medicine, School of MedicineTumor-induced Osteomalacia (TIO) and Epidermal Nevus Syndrome with osteomalacia (ENS) are rare conditions in which ectopic production of FGF23 by tumor (TIO) and bone (ENS) lead to renal phosphate wasting, impaired 1,25(OH)2D synthesis, osteomalacia, fractures, weakness, fatigue and decreased mobility. In an ongoing open-label Phase 2 study (NCT02304367), 17 adults were enrolled and treated with burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were change in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. The per protocol (PP) analysis included 14/17 subjects who received 0.3-2.0 mg/kg burosumab every 4 weeks (W). Three subjects were excluded: 1 received subthreshold dosing (0.3 mg/kg at Day 0 and 0.15 mg/kg at W8, W32, and W72); 2 were diagnosed with X-linked hypophosphatemia post-enrollment. Ten subjects in the PP group had paired bone biopsies at baseline and W48. Mean ± SE histomorphometric values for the 8/10 subjects with osteomalacia at baseline were 20.4 ± 4.2 µm for osteoid thickness (OT), 23.0 ± 7.2% for osteoid volume/bone volume (OV/BV), and 66.1 ± 10.6% for osteoid surface/bone surface (OS/BS); baseline median (Q1, Q3) for mineralization lag time (MLT) was 1672 (1102, 2929) days. At W48, histomorphometric indices improved as shown by mean percentage changes in OT (37%), OV/BV (40%), OS/BS (-5%), and MLT (median percentage change -78%). Serum phosphorus, fatigue, and physical functioning are reported for the PP group. Mean (SD) serum phosphorus was 1.5 (0.3) mg/dL at baseline and 2.6 (0.8) mg/dL when averaged across the mid-point of the dose interval through W24. After W24, serum phosphorus, assessed only at the end of the dose interval, maintained this increase through W72. Mean (SD) Global Fatigue Score decreased from 5.3 (2.8) at baseline to 3.6 (2.9) at W48 (p=0.020) and to 3.3 (2.7) at W72 (p=0.004). The SF-36 mean (SD) physical component summary score increased from 34 (11) at baseline to 39 (10) at W48 (p=0.059) and to 42 (10) at W72 (p=0.003). Mean (SD) vitality score increased from 41 (14) to 47 (12) at W48 (p=0.075) and to 49 (12) at W72 (p=0.012). The mean (SD) number of sit-to-stand repetitions increased from 6.9 (4.0) at baseline to 8.6 (4.2) at W48 (n=10; p=0.004). By W72, all 17 subjects had ≥1 adverse event (AE). There were 13 serious AEs in 6 subjects, none were considered drug-related. Tumor progression occurred only in subjects with a history of tumor progression prior to enrollment. One subject discontinued treatment prior to W48 to treat tumor progression with chemotherapy. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in serum phosphorus, osteomalacia, mobility, quality of life, and reductions in fatigue.Item Reply to: Burosumab for Tumor-Induced Osteomalacia: not Enough of a Good Thing(Wiley, 2021) Jan de Beur, Suzanne M.; Miller, Paul D.; Weber, Thomas J.; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Rauch, Frank; Luca, Diana; Cimms, Tricia; Scott Roberts, Mary; San Martin, Javier; Carpenter, Thomas O.; Medicine, School of MedicineItem Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia(Endocrine Society, 2022) Linglart, Agnès; Imel, Erik A.; Whyte, Michael P.; Portale, Anthony A.; Högler, Wolfgang; Boot, Annemieke M.; Padidela, Raja; van’t Hoff, William; Gottesman, Gary S.; Chen, Angel; Skrinar, Alison; Scott Roberts, Mary; Carpenter, Thomas O.; Medicine, School of MedicinePurpose: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH. Methods: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab. Results: Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity. Main conclusions: In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab.Item X-Linked Hypophosphatemia Caused by the Prevailing North American PHEX Variant c.*231A>G; Exon 13-15 Duplication Is Often Misdiagnosed as Ankylosing Spondylitis and Manifests in Both Men and Women(Wiley, 2022-11-02) McCrystal Dahir, Kathryn; Black, Margo; Gottesman, Gary S.; Imel, Erik A.; Mumm, Steven; Nichols, Cindy M.; Whyte, Michael P.; Medicine, School of MedicineInactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH.