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Abstract Context Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Hyperparathyroidism (HPT) including secondary HPT (SHPT) and tertiary HPT (THPT) in TIO patients, which is believed to be associated with phosphate supplementation, has not been well documented. Objectives To clarify the prevalence, clinical characteristics, and risk factors for HPT in a large cohort of Chinese patients with TIO in our hospital. Design, setting, and participants This retrospective study enrolled 202 patients with TIO. Main outcome measurements Occurrence of HPT in patients with TIO. Results HPT was observed in 91 patients (91/202, 45.1%): 84 patients (41.6%) with SHPT and 7 patients (3.5%) with THPT. All patients with THPT underwent parathyroidectomy and only 1 patient experienced recurrence. Compared with patients without HPT, patients with SHPT had longer disease duration, higher rate of phosphate and calcitriol supplementation, lower serum calcium, lower urine calcium excretion, and higher urine phosphate excretion. Compared with patients with SHPT, patients with THPT had even longer disease duration and a higher rate of phosphate and calcitriol supplementation. PTH levels showed positive correlation with intact FGF23 and 1,25-dihydroxyvitamin D levels, but not 25-hydroxy vitamin D level in patients with TIO. Multivariate logistic regression analysis showed that long disease duration and phosphate supplementation were independently associated with occurrence of HPT in patients with TIO. Further logistic regression analysis and restricted cubic spline model revealed dose-response relationship between cumulative dose of phosphate supplementation and PTH levels. Conclusions HPT is common in patients with TIO. To avoid the occurrence of HPT in patients with TIO, timely diagnosis and tumor resection is necessary and an excessive dose of phosphate supplementation is not suggested before surgery.

Summary 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) 2 vitamin D 3 , 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.

Key Points Paraneoplasias are caused by soluble factors produced by tumour cells or are the consequence of an immune reaction against these cells An underlying malignancy should be sought if musculoskeletal symptoms do not show an adequate response to therapy Arthritis, myositis, periostitis, fasciitis and osteomalacia can all be musculoskeletal manifestations of a paraneoplastic disease Due to the properties of soluble factors produced by tumour cells, some paraneoplasias show a characteristic involvement of specific musculoskeletal tissues (e.g. VEGF inducing HOA or FGF23 inducing TIO) Despite their rarity, knowledge of distinct clinical patterns of paraneoplasias is essential for the rheumatologist, because their recognition allows for a timely diagnosis and potentially life-saving therapy The dissection of underlying molecular mechanisms can provide insights in the pathogenesis for rheumatic as well as neoplastic diseases Although paraneoplastic syndromes are rare, it is important that rheumatologists can recognise the typical clinical patterns of these syndromes in their rheumatic disease patients to allow for timely diagnosis and potentially life-saving therapy. Here, the authors focus on well-defined paraneoplastic musculoskeletal syndromes for which the evidence of a causal relationship to an underlying tumour is not only based on a temporal relationship but also on underlying pathomechanisms. For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective tissue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23.

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.

Purpose This article aims to provide a comprehensive review of the management challenges associated with Spinal Phosphaturic Mesenchymal tumors (PMTs) and evaluates the surgical management outcomes for this rare entity linked to Tumor-induced osteolysis. The primary objective of this study is to enhance the familiarity of treating physicians with the clinical features, diagnosis, and treatment options for Spinal PMTs. Methods A retrospective analysis was conducted, reviewing electronic medical records of patients diagnosed with spinal PMTs at our hospital between January 2019 and December 2022. The data collected included demographic information, clinical presentation, radiological findings, surgical details, and follow-up outcomes. Results A total of three cases of Spinal PMTs causing Tumor-induced osteomalacia were identified. The diagnosis of Spinal PMTs presented challenges, with incidental detection often occurring during routine imaging. Surgical management was undertaken, resulting in successful symptom resolution and normalization of phosphate levels. The application of 68 Ga-DOTA-TATE PET/CT scans facilitated tumor localization, aiding in surgical planning. Spinal PMTs demonstrated a favorable response to surgical intervention. Conclusion Spinal PMTs play a significant role in Tumor-induced osteolysis, warranting timely and accurate diagnosis. Although diagnosing Spinal PMTs presents challenges, surgical management has proven to yield favorable outcomes, effectively alleviating symptoms and restoring phosphate levels. A multidisciplinary approach and continued vigilance are essential in ensuring early diagnosis, effective treatment, and long-term monitoring for patients affected by spinal PMTs.

Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate mineralization of the skeleton, is caused by different processes leading to decreased available mineral (calcium and/or phosphate) or enzymatic alterations. Vitamin D deficiency, which remains the major cause of altered mineralization leading to inadequate intestinal calcium and phosphate absorption, may be also associated with other conditions primarily responsible for abnormal mineralization. Given the reality of widespread vitamin D inadequacy, a full biochemical assessment of mineral metabolism is always necessary to rule out or confirm other conditions. Both too-high or too-low serum alkaline phosphatase (ALP) levels are important for diagnosis. Osteomalacic syndrome is reversible, at least in part, by specific treatment. Osteomalacia and bone mineralization themselves constitute largely unexplored fields of research. The true prevalence of the different forms of osteomalacia and the recovery after proper therapy have yet to be determined in the real world. Although non-invasive techniques to assess bone mineralization are not available in clinical practice, the systematic assessment of bone quality could help in refining the diagnosis and guiding the treatment. This review summarizes what is known of osteomalacia recent therapeutic developments and highlights the future issues of research in this field.

Purpose The aim of this study is to review the clinical and laboratory characteristics, diagnostic and treatment modalities of tumor-induced osteomalacia (TIO) cases managed in a single center. Material methods Demographic and clinical features, biochemical findings, diagnostic procedures, treatment modalities, and outcomes of nine patients who had the diagnosis of TIO were reviewed retrospectively. Results Mean age of the study group (F/M: 4/5) was 45.8 ± 10.8 years, and mean time from the onset of symptoms to diagnosis was 4.7 ± 2.8 years. The clinical manifestations were muscle weakness and difficulty in walking (8/9), hip pain (3/9), multiple fractures (2/9), stress fracture (2/9). Mean plasma phosphorus concentration was 1.28 ± 0.4 mg/dl at presentation. We performed radionuclide imaging modalities (18F-FDG PET/CT, Ga68-DOTATATE PET/CT, octreotide scintigraphy) in seven of nine patients, and tumor was detected in all. Lower extremity ( n  = 6; %67), head region ( n  = 2; %22) and thorax ( n  = 1; %11) were the tumor locations of our cases. Eight patients underwent surgery and remission was achieved postoperatively in all of the operated patients and plasma phosphorus level normalized in 4 ± 2 days. Pathological examination revealed mesenchymal tumors with different subtypes. Recurrence occurred in three patients at 13 ± 10.5 months after the first surgery. Two patients were reoperated and radiotherapy was also performed in one of them. Conclusion Hypophosphatemia necessitates careful evaluation for the etiology. TIO is one of the important causes of adult-onset hypophosphatemic osteomalacia. Diagnosis of TIO is essential because the laboratory and clinical findings resolve after appropriate treatment.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO’s incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.

Phosphaturic mesenchymal tumors (PMTs) are extremely rare mesenchymal tumors of soft tissue and bone that cause tumor-induced osteomalacia (TIO). Some of these tumors are completely asymptomatic and may grow undetected unless they become large enough to cause pain or discomfort. This type of tumor is crucial to diagnose in patients being treated for phosphate metabolism disorders and are a rare reason why patients seek medical help owing to pain. Here, we report the details of a patient with progressive bone pain caused by a PMT originating in the left femur.