Long-term use of burosumab for the treatment of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumoral overproduction of FGF-23. Due to local recurrence, we describe the long-term efficacy and safety profile of burosumab, an anti-FGF-23 monoclonal antibody, in a TIO patient after three unsuccessfully surgical attempts. INTRODUCTION: TIO is a rare paraneoplastic syndrome caused by tumoral overproduction of fibroblast growth factor 23 (FGF23), resulting in hyperphospaturia, hypophosphatemia, and osteomalacia. Surgery is the only definitive treatment, but tumor can locally recur, even after years from primary surgery. Furthermore, some tumors cannot be removed by surgery due to their location. METHODS: We describe the case of a 54-year-old woman affected by recurrent TIO who, after three unsuccessful surgical attempts of tumor removal, was treated with burosumab, an anti-FGF-23 monoclonal antibody. RESULTS: The patient was referred to our Bone Unit after experiencing several fractures in different sites, both traumatic and non-traumatic. At the time of first evaluation, at the age of 46, serum-phosphate (SP) was 1.2 mg/dL (reference range (RR) 2.5-4.5), 24-h urinary phosphate was 842 mg (RR 400-1000), and intact-FGF-23 was 117 pg/mL (RR 25-45). Imaging showed a metabolic pre-sacral lesion that firstly underwent to exploratory laparotomy. Then, patient underwent to surgical excision of tumor. After 18 months of well-being, tumor relapsed and even the subsequent surgery was not able to completely remove it. Since 2015, patient was maintained in phosphorus supplements and 1,25(OH)2vitamin D3, but SP levels never normalized. In September 2019, she was started on burosumab, initially at the dose of 0.3 mg/kg/month, progressively increased to the current 0.8 mg/kg/month, with great improvement of pain, physical performance, and normalization of SP levels. Burosumab was temporary and cautionary discontinued for COVID-19 pneumonia, with a worsening of SP. After restart of burosumab, biochemistry returned to normal. CONCLUSIONS: To our knowledge, this is the first European patient affected by TIO treated with burosumab for more than 2 years. Burosumab is a promising therapy in the medical treatment of TIO refractory or not eligible for definitive surgery, with good efficacy and safety profile.

Phosphatonins: From Discovery to Therapeutics.

OBJECTIVE: Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone, 1,25-dihydroxyvitamin D, and phosphatonins, especially fibroblast growth factor 23 (FGF23). These hormones facilitate maintenance of phosphate homeostasis. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment. METHOD: A focused literature search of PubMed was conducted. RESULTS: Phosphatonins including FGF23, secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 7 play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the proximal renal tubule, and thus, it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults. CONCLUSION: The treatment paradigm for XLH and TIO is changing based on data from recent clinical trials. Research suggest that burosumab is effective and safe for pediatric and adult patients with XLH or TIO.

Improvement in the mobility of a patient with fibroblast growth factor 23-related hypophosphatemic osteomalacia and decompensated liver cirrhosis in response to burosumab: a case report.

Acquired fibroblast growth factor (FGF) 23-related hypophosphatemic osteomalacia is characterized clinically by muscle weakness, bone pain, and fractures. Its biochemical features include hypophosphatemia, caused by renal phosphate wasting, and inappropriately normal or low 1,25-dihydroxy-vitamin D levels. Recently, burosumab, a fully human monoclonal antibody targeting FGF23, was approved for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. We report the case of a 75-year-old Japanese woman with decompensated liver cirrhosis and hepatic encephalopathy, caused by primary biliary cholangitis, who complained of back pain and limited mobility resulting from multiple vertebral fractures. She was not receiving iron infusion therapy and denied alcohol consumption. The patient exhibited hypophosphatemia with a low tubular maximum reabsorption of phosphate per unit glomerular filtration rate (TmP/GFR) and a high circulating concentration of FGF23. Conventional therapy with alfacalcidol and oral phosphate slightly improved her serum phosphate concentration and back pain, but she experienced a hip fracture, causing her to become wheelchair-dependent. Burosumab was initiated 8 weeks after the hip fracture, which increased her serum phosphate concentration and TmP/GFR. Her mobility gradually improved, such that she could walk without a cane after 16 weeks of treatment. Her lumbar bone mineral density increased after 48 weeks. Hepatic encephalopathy developed once before the initiation of treatment and twice after the initiation of the therapy, but her liver function was preserved. This is the first study to report the efficacy and safety of burosumab treatment for FGF23-related hypophosphatemic osteomalacia with decompensated liver cirrhosis.

FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho.

The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.

Hypophosphatemic osteomalacia, a side effect of iron carboxymaltose administration.

Carboxymaltose iron (Ferinject®) is a formulation for intravenous (iv) administration, used for the treatment of iron deficiency anemia and/or iron deficiency when oral administration of iron is not effective or due to intolerance. Its safety profile is excellent with few, but not nonexistent, side effects. Hypophosphatemia has been described as one of them. It is usually mild, transient and asymptomatic. However, in some cases it may be accompanied by nausea, asthenia, in addition to muscular and neurological symptoms and hematological alterations. It is, therefore, a potentially serious adverse effect whose prevalence is unknown and which requires high clinical suspicion to be detected.

FGF23 and Hypophosphatemic Rickets/Osteomalacia.

PURPOSE OF REVIEW: X-linked hypophosphatemia and tumor-induced osteomalacia are diseases characterized by hypophosphatemia with impaired proximal tubular phosphate reabsorption. Complete resection of responsible tumors is the first-line therapy for patients with tumor-induced osteomalacia. In contrast, phosphate and active vitamin D have been used for patients with X-linked hypophosphatemia and inoperable ones with tumor-induced osteomalacia. The purpose of this review is to summarize the pathogenesis of these diseases and discuss about the new treatment. RECENT FINDINGS: Excessive FGF23 production has been shown to underline several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemia and tumor-induced osteomalacia. Burosumab, an anti-FGF23 monoclonal antibody, was approved for clinical use, while the indications of burosumab are different depending on countries. The inhibition of excessive FGF23 activity has been approved as a new therapy for several kinds of hypophosphatemic diseases. Further studies are necessary to clarify the long-term effects and safety of burosumab.

Mineralized tissues in hypophosphatemic rickets.

Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.

Effectiveness of intramuscular ergocalciferol treatment in a patient with osteomalacia and insufficiency fractures due to severe vitamin D deficiency after bariatric surgery.

Vitamin D (vitD) deficiency and bone loss may occur after bariatric surgery and hence, supplementation with high oral doses of vitD may be required. Alternatively, intramuscular depot ergocalciferol, which slowly releases vitD and bypasses the gastrointestinal tract, could be administrated. We present a case of severe vitD deficiency-osteomalacia after gastric bypass operation for morbid obesity, treated with ergocalciferol intramuscularly. A 45-year-old woman was presented with hip pain and muscle weakness, which led ultimately to immobilization in a wheelchair. Fifteen years ago, she underwent roux-en-Y gastric by-pass for morbid obesity. Occasionally, she was treated with multivitamin supplements. On admission, iron deficiency anaemia, vitD deficiency (25OHD: 3.7 ng/ml) and secondary hyperparathyroidism were revealed. Bone turnover markers (BTM) were elevated. Radiological evaluation demonstrated insufficiency fractures on the pubic and left femur and reduced BMD. Osteomalacia due to vitD deficiency and calcium malabsorption were diagnosed. Calcium citrate 500 mg qid and intramuscular ergocalciferol 600,000 IU every 20 days were initiated. One month later, musculoskeletal pain and weakness were resolved and the patient was mobilized. Few months later, vitD, BTM and BMD showed substantial improvement. Intramuscular ergocalciferol administration can improve the clinical and biochemical status and thus, is suggested to prevent and/or treat osteomalacia in such patients.

[MODERN ISSUES OF D-VITAMIN SIGNIFICANCE IN DEVELOPMENT OF FULERUM-MOVE DEVICES OF INFANTS, CHILDREN AND ADOLESCENTS ( REVIEW)].

The purpose of this review is the study of literature for the current data on the metabolism of vitamin D and its role in development of bone tissue in children. The role of the main marker enabling assessing 25(OH)D concentration in the body the reference values has been analyzed. Summarizing the literature data, we may say that vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a mayor impact on health of infants, children and adolescents.

Severe hypophosphatemia induced by denosumab in a patient with osteomalacia and tenofovir disoproxil fumarate-related acquired Fanconi syndrome.

Denosumab, a novel agent that inhibits osteoclasts, reduces the risk of fracture in patients with osteoporosis. However, worsening of hypophosphatemia and other symptoms may be induced by denosumab in patients with pre-existing hypophosphatemic osteomalacia. A 58-year-old man with hepatitis B presented with diffuse bone pain and muscle weakness. Denosumab was prescribed by the orthopedist according to documented low bone mass and spine compression fracture. After administering denosumab, the patient's bone pain worsened, and he later developed a right tibia stress fracture. His condition was diagnosed as adult-onset hypophosphatemic osteomalacia complicated by multiple bone fractures, which resulted from Fanconi syndrome with proximal tubulopathy due to tenofovir disoproxil fumarate (TDF) treatment for his hepatitis B. Denosumab use leads to aggressive hypophosphatemic osteomalacia and the complication of stress fractures, because of its effects on bone resorption. Physicians should be aware that in patients with chronic hepatitis B monoinfection who are administered TDF therapy, bone pain or fracture is possible but preventable by timely monitoring of serum phosphate levels. Denosumab should not be used in patients with untreated osteomalacia or vitamin D deficiency, as it may lead not only to hypocalcemia but also to hypophosphatemia in these patients.

Phosphate wasting disorders in adults.

A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.

[Osteomalacia-Clinical aspects, diagnostics and treatment]. / Osteomalazie ­ Klinik, Diagnostik und Therapie.

Osteomalacia is a bone disease caused by impaired skeletal mineralization. Vitamin D dependent types have to be distinguished from hypophosphatemic forms. Typical signs and symptoms include diffuse bone pain, muscle weakness and fragility fractures. The fracture pattern in osteomalacia is typically different from that of osteoporosis. Fragility fractures of the pelvis, sacrum, distal parts of the foot, proximal tibia and ribs are indicators for osteomalacia, whereas femoral neck and vertebral fractures (wedged vertebra, fish vertebra, vertebra plana and cover plate impression fractures) are typical for osteoporosis. Unspecific clinical features may be the reason for a delayed diagnosis. The correct classification of the complaint is dependent on the knowledge of the pathophysiology of osteomalacia and performance of additional bone-specific examinations. Determination of specific laboratory parameters should follow a rational algorithm, supplemented by imaging methods and a bone biopsy.

[Rickets/Osteomalacia. Non-skeletal effects of vitamin D.]

A variety of epidemiological studies and meta-analyses have shown that vitamin D insufficiency or deficiency not only affects bone and mineral metabolism, but is also linked to sarcopenia, metabolic diseases such as diabetes, obesity, and metabolic syndrome, cancer, autoimmune disease, and other diseases. There has been accumulating evidence that vitamin D deficiency, defined as a serum 25(OH)D value below 20 ng/mL, is a significant risk factor for each of these diseases. However, vitamin D supplementation has not shown a therapeutic effect in any of these diseases, and a detailed cause-and-effect relationship remains elusive. Future studies should consider non-skeletal effects when investigating cutoff levels of serum 25(OH)D for therapeutic intervention in vitamin D insufficiency and deficiency, the required supplement dose, and the length of supplementation.

Tumor-induced Osteomalacia in a 3-Year-Old With Unresectable Central Giant Cell Lesions.

Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia involving overproduction of fibroblast growth factor 23. TIO has been described largely in adults with small mesenchymal tumors. We report a case of TIO in a child who presented with knee pain and radiographic findings concerning for rickets, and was found to have maxillomandibular giant cell lesions. The patient was treated with oral phosphorus and calcitriol, surgical debulking, and intralesional corticosteroids, which resulted in tumor regression and normalization of serum fibroblast growth factor 23 and phosphorus. This case illustrates the occurrence of this rare paraneoplastic syndrome in children and adds to our knowledge about clinical manifestations and pathologic findings associated with pediatric TIO.

Hypophosphatemic osteomalacia: a case simulating anklylosing spondylitis treated with anti-TNF therapy.

In this case, a young male patient diagnosed as hypophosphatemic osteomalacia and ankylosing spondylitis (AS) will be assessed by literature. A 32-year-old male patient who had been previously diagnosed as ankylosing spondylitis and hypophosphatemic osteomalacia was admitted to our clinic. In the beginning of the disease, he complained of pain on the first metatarsal bone and low back. Sacroiliac magnetic resonance (MR) images were interpreted as sacroiliitis. He was diagnosed as AS, and referred to many hospitals and received several therapies. He did not benefit from the treatment and his complaints worsened. The human leukocyte antigen (HLA) B-27 test was negative and alkaline phosphatase level was high. Old femur fractures were reported in the whole body bone scintigraphy. In addition, the patient was diagnosed with osteomalacia. While the patient was receiving vitamin D, oral phosphate, anti-tumor necrosis factor therapy was added. Patient's diagnosis was reevaluated. His final diagnosis was hypophosphatemic osteomalacia instead of ankylosing spondylitis.

FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23-related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism.