Reply to: Burosumab for Tumor-Induced Osteomalacia: not Enough of a Good Thing.
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SUBMITTER: Jan de Beur SM
PROVIDER: S-EPMC9290665 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
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Reply to: Burosumab for Tumor-Induced Osteomalacia: not Enough of a Good Thing.
Jan de Beur Suzanne M SM Miller Paul D PD Weber Thomas J TJ Peacock Munro M Insogna Karl K Kumar Rajiv R Rauch Frank F Luca Diana D Cimms Tricia T Roberts Mary Scott MS Martin Javier San JS Carpenter Thomas O TO
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20210524 12
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Project description:Tumor-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. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
| S-EPMC8247961 | biostudies-literature
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| S-EPMC4605441 | biostudies-literature
Project description:Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed.
| S-EPMC3433741 | biostudies-literature
Project description:Patients with tumor-induced osteomalacia (TIO), an acquired paraneoplastic condition characterized by osteomalacia due to hypophosphatemia, exhibit a similar clinical picture to those with X-linked hypophosphatemic rickets/osteomalacia (XLH). The human monoclonal anti-fibroblast growth factor 23 (FGF23) antibody burosumab (KRN23) increases serum phosphate and improves bone turnover, fracture healing, pain, and physical function in XLH patients by inhibiting circulating FGF23; thus, burosumab is expected to be an effective treatment for TIO. We report here an interim analysis of a multicenter, open-label, intraindividual dose-adjustment study of burosumab (0.3 to 2.0 mg/kg every 4 weeks) in Japanese and Korean TIO patients. The primary endpoint was the fasting serum phosphate level at each visit. Key secondary endpoints were changes over time in bone biomarkers, pharmacodynamic markers, bone histomorphometric parameters, motor function, and patient-reported outcomes. Safety was assessed based on treatment-emergent adverse events (TEAEs). Thirteen patients received burosumab treatment, of whom 4 underwent bone biopsy. The mean dose after week 112 was approximately 1.0 mg/kg. After the first burosumab administration, mean serum phosphate levels increased and remained above the lower limit of normal and in the normal range from weeks 14 to 112. Bone biomarkers initially increased, reaching maximum values at week 16 or 24, and then gradually decreased. After burosumab treatment, patients were able to walk further (evaluated by the 6-minute walk test), reported decreased pain levels, and showed a tendency toward healing of baseline fractures and pseudofractures. Two patients discontinued, one each due to disease progression and consent withdrawal. Burosumab was generally well tolerated, with no treatment-related TEAEs of grade ≥3 and no treatment-related serious AEs. In conclusion, the interim results of this first study of burosumab to treat TIO patients indicate that this drug has the potential to provide clinical benefit for patients with unresectable tumors. The full study results are eagerly anticipated. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
| S-EPMC7988547 | biostudies-literature
Project description:Tumor induced osteomalacia is a rare acquired disease. The cause is a mesenchymal tumor secreting fibroblast growth factor 23 (FGF23). An excessive amount of FGF 23 disrupts the metabolism of phosphorus and vitamin D, which leads to severe paraneoplastic syndrome, manifested in the form of multiple fractures, severe pain in the bones and generalized myopathy. With oncogenic osteomalacia, a complete cure is possible with radical resection of the tumor. Unfortunately, localization, small size of formations and rare frequency of occurrence lead to the fact that the disease remains unrecognized for a long time and leads to severe, disabling consequences. A step-by-step approach to diagnosis improves treatment outcomes. First, a thorough anamnesis is collected, then functional visualization is performed and the diagnosis is confirmed by anatomical visualization of the tumor. After that, the method of choice is a surgical treatment. If resection is not possible, then conservative therapy with active metabolites of vitamin D and phosphorus salts is indicated. New therapeutic approaches, such as the antibody to FGF23 or the pan-inhibitor of receptors to FGF, are actively developing. This article provides an overview of modern approaches to the diagnosis and treatment of this disease.
| S-EPMC9762448 | biostudies-literature
Project description:Abstract Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome wherein small tumors secrete excess fibroblast growth factor 23 (FGF23) leading to hypophosphatemia, osteomalacia, bone pain, fractures, and muscle weakness. Burosumab is an anti-FGF23 monoclonal antibody approved for treatment of TIO. We report end of study (EOS) data from the open-label phase 2 UX023T-CL201 trial (NCT02304367) of burosumab in adults with TIO. In UX023T-CL201, participants received burosumab (0.3–2.0 mg/kg) by subcutaneous injection every 4 weeks for 48 weeks with an extension up to 300 weeks (∼6 years). Co-primary endpoints were change in serum phosphorus at Week 24 and change in excess osteoid by trans-iliac crest bone biopsy at Week 48. Additional endpoints included changes in bone biomarkers, activity on radionucleotide bone scan representing fractures/pseudofractures, patient-reported outcomes, and safety measures. This analysis included 14/17 UX023T-CL201 participants; excluding those with other diagnoses (n=3). Mean (SD) serum phosphorus improved from 1.6 (0.5) mg/dL at baseline to 2.3 (0.5) mg/dL when averaged across the mid-point of the dose interval through Week 24 (co-primary endpoint). Levels further improved (2.6 [0.4] mg/dL; n=7) to within the normal range (2.5–3.6 mg/dL) at Week 240. Most measures of osteomalacia improved at Week 48 (co-primary endpoint), including osteoid/bone volume, osteoid thickness, and mineralization lag time. However, osteoid surface/bone surface showed no change. Bone biomarkers (P1NP, CTx, BALP) followed similar trends. Upon initiation of burosumab, markers briefly increased by Week 24 as bone healing began, then gradually decreased with further treatment, reaching normal (P1NP, CTx) or near-normal (BALP) ranges by Week 240. At baseline, 249 areas of increased radionucleotide uptake indicating fracture activity were detected across 14 participants. By Week 144, 36% (72/201) and 13% (26/201) regions of abnormal uptake were fully or partially restored, respectively. By EOS, further reduction of active fractures and fewer new areas of uptake were observed. New fractures at Week 144 were observed in a single participant (considered a burosumab partial responder) and between Week 144 and EOS in another participant unrelated to burosumab (car accident). Participants reported sustained mean reduction from baseline pain at Week 240 per Brief Pain Inventory and significantly per SF-36 Bodily Pain score. Significant reductions in baseline fatigue at Week 240 were reported per Brief Fatigue Inventory and SF-36 Vitality scores. SF-36 physical health (Role Physical, Bodily Pain, Component Score) and mental health (Social Function, Vitality) significantly improved from baseline at Week 240. The observed safety profile of long-term burosumab in participants with TIO was consistent with the known safety profile of burosumab and similar to patients with XLH. Long-term burosumab therapy was associated with improved serum phosphorus, osteomalacia, bone turnover, fracture incidence and healing, health-related quality of life, and reductions in pain and fatigue in adults with TIO. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.
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Project description:Tumor-induced osteomalacia (TIO) is a rare, acquired condition of phosphate wasting due to phosphaturic mesenchymal tumors. Because the incidence and prevalence of TIO is unknown, we conducted an observational cohort study using national Danish health registers for the period 2008 to 2018 to obtain such information. The study also aimed to describe the demographics of the TIO population and the prognosis. The operational definition was based on hypophosphatemia or adult osteomalacia diagnoses, combined with prescriptions used in the initial management and procedures consistent with advanced imaging used for locating tumors. The incidence of TIO in Denmark was found to be below 0.13 per 100,000 person years for the total population of the country and 0.10 per 100,000 in adult-onset disease. The prevalence of TIO was estimated to be no more than 0.70 per 100,000 persons for the total population and 0.43 per 100,000 in adults. In 2018, there were a maximum of nine new cases of TIO in Danish adults. Mortality was low but few patients fulfilled the protocol cure criterion during the observation period. TIO has no ICD-10 code and limitations to the study include lack of information on serum biochemistry and on the use of phosphate supplements. Strengths include the use of long-term longitudinal, national hospital and prescription data from a country with universal healthcare. Given the very small patient population with TIO and the known delay to diagnosis and cure, management of patients with suspected TIO should be centralized.
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Project description: Not available
| S-EPMC8183716 | biostudies-literature
Project description:Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemic osteomalacia, which is associated with impaired bone matrix mineralization. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by over-secretion of FGF23 from a tumor. Burosumab, a fully human monoclonal antibody with activities against FGF23, was initially approved in Japan before the rest of the world for treatment of FGF23-associated hypophosphatemic osteomalacia by TIO. We report here a patient with a 15-year history of non-remission TIO initially treated with conventional therapy who was then switched to burosumab treatment. Persistent hypophosphatemia and a relative low level of osteocalcin (bone Gla protein, BGP) compared with bone alkaline phosphatase (BAP) level, indicating poor matrix mineralization, developed during long-term conventional therapy. Repeated surgical and stereotactic body radiation treatments did not result in complete resection of the causable tumor, and bone mineral density (BMD) gradually decreased. Ultimately, burosumab treatment was administered and the serum Pi concentration immediately normalized, while both BGP and BMD also showed a good response. This is first known case report of the detailed efficacy of burosumab for nonremission TIO as an alternative to conventional therapy.
| S-EPMC7701316 | biostudies-literature
Project description:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. It is curable by excision of the causative tumor. However, a few cases may persist or relapse after tumor resection. We aimed to investigate the rate of these events and related factors. We retrospectively studied TIO patients treated with surgery in a tertiary hospital. TIO was established based on a pathologic examination or the reversion of hypophosphatemia. Refractory TIO patients consisted of those with nonremission or recurrent hypophosphatemia after surgery. A total of 230 patients were confirmed as having TIO. After primary surgery, 26 (11.3%) cases persisted, and 16 (7.0%) cases recurred. The overall refractory rate was 18.3%. The median time of recurrence was 33 months. Compared with patients in the recovery group, patients in the refractory group were more likely to be female (59.5% versus 41.0%, p = .029) and have a lower serum phosphate level (0.44 ± 0.13 versus 0.50 ± 0.11 mmol/L, p = .002). The refractory rate was lowest in head/neck tumors (7.5%) and highest in spine tumors (77.8%). Regarding the tissue involved of tumor location, the refractory rate was higher in tumors involving bone than tumors involving soft tissue (32.7% versus 7.0%, p < .001). The outcomes of malignant tumors were worse than those of benign tumors (p < .001): nonremission rate, 21.4% versus 9.7%; recurrence rate, 28.6% versus 6.5%. In the multivariate regression analysis, female sex, spine tumors, bone tissue-involved tumors, malignancy, and low preoperation serum phosphorus levels were identified as risk factors for refractory outcomes. High preoperative fibroblast growth factor 23 (FGF23) levels were also associated with refractory after adjusting for involving tissue and tumor malignancy. In summary, we are the first to report the rate and clinical characteristics of refractory TIO in a large cohort. For patients with multiple risk factors, especially spine tumors, clinical practitioners should be aware of a poor surgical prognosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
| S-EPMC7140180 | biostudies-literature