Osteomalacia

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..

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.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by hypersecretion of fibroblast growth factor 23 (FGF23) by typically benign phosphaturic mesenchymal tumors (PMTs). FGF23 excess causes chronic hypophosphatemia through renal phosphate losses and decreased production of 1,25-dihydroxy-vitamin-D. TIO presents with symptoms of chronic hypophosphatemia including fatigue, bone pain, weakness, and fractures. Definitive treatment is surgical resection of the PMT with wide margins. Other therapeutic options are necessary when the tumor is unable to be localized, not amenable to complete resection, or when the patient is not a good surgical candidate. Alternative ablative approaches such as radiotherapy, radiofrequency ablation, and cryoablation, have been used with variable success and limited follow up. Medical management is warranted both prior to definitive therapy and in non-operable cases to improve symptoms and allow for bone remineralization. Oral phosphate and calcitriol were the mainstay of medical therapy, however, the development of burosumab, a monoclonal blocking antibody to FGF23, has introduced an approved therapy that improves hypophosphatemia and symptoms in patients with TIO. In select cases, cinacalcet can be an effective adjuvant to phosphate and calcitriol. Continued monitoring for tumor growth is necessary while on medical therapy. Infigratinib, a selective FGFR tyrosine-kinase inhibitor targeting a causative tumoral fusion protein, can reverse the biochemical findings of TIO and possibly reduce tumor mass; however, its use is constrained by serious side effects. Overall, innovations in medical and interventional treatments have broadened therapeutic options for patients with PMTs, particularly in cases where a curative surgical resection is not possible.