Skeletal fluorosis: an uncommon cause, yet a rescue treatment?

PURPOSE: Skeletal fluorosis (SF) results from chronic exposure to fluoride (F-) causing excessive aberrantly mineralized brittle bone tissue, fractures, and exostoses. There is no established treatment other than avoiding the source of F-. Still, excess F- can persist in bone for decades after exposure ceases. CASE PRESENTATION: A 50-year-old woman presented with multiple, recurrent, low AQ2 trauma fractures yet high radiologic bone mineral density. Serum F- was elevated, and osteomalacia was documented by non-decalcified transiliac biopsy. She reported intermittently "huffing" a keyboard cleaner containing F- (difluoroethane) for years. Following cessation of her F- exposure, we evaluated the administration of the parathyroid hormone analog, abaloparatide, hoping to increase bone remodeling and diminish her skeletal F- burden. CONCLUSION: Due to the prolonged half-life of F- in bone, SF can cause fracturing long after F- exposure stops. Anabolic therapy approved for osteoporosis, such as abaloparatide, may induce mineralized bone turnover to replace the poorly mineralized osteomalacic bone characteristic of SF and thereby diminish fracture risk. Following abaloparatide treatment for our patient, there was a decrease in bone density as well as a reduction in F- levels.

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study.

Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

Long-Term Follow-Up Data of Tumor-Induced Osteomalacia Managed with Surgery and/or Radiofrequency Ablation from a Single Center.

Data on radiofrequency ablation (RFA) in tumor-induced osteomalacia (TIO) are restricted to case reports (~ 11 patients) and long-term follow-up data are further scarce. We describe our experience on managing TIO from a tertiary care center in India. Retrospective study of patients with localized TIO was performed and clinical, biochemical, treatment and follow-up details were retrieved. Normalization of serum phosphorus in absence of phosphate supplementation was defined as remission. Of 33 patients (23 males), 24 patients underwent surgery as first-line treatment, and early remission, delayed remission (> 1 month for phosphorus normalization) and persistence were observed 12, 3, and 9 patients at a median follow-up of 5 (4-9) years. The gender, age, tumor size, location of tumors and FGF23 levels were not statistically different in patients who were in remission after surgery versus those with persistent disease. Second/third line treatment included conventional medical treatment and/or repeat surgery (n = 3), radiotherapy (n = 3), peptide receptor radionuclide therapy (n = 1), RFA (n = 1). Two patients had transient worsening (weeks) of weakness post-surgery. 10 patients underwent RFA (first-line n = 9); at the last follow-up 5 (4-10) years, 7 are in remission. Two of three persistent disease patients had large tumors (5.6 and 3.6 cm). There were no RFA-related complications except local ulcer in one. Although persistent disease was present in a few patients in both arms, there was no recurrence in either RFA or surgical cohort. RFA provide durable response similar to surgery, persistence requires multi-modality treatment.

A Rare Association Between Osteomalacia, Phosphaturic Mesenchymal Tumor, and Ovarian Cancer: A Case Report and Literature Review.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia, bone mineralization disorders with increased risk of fragility fractures, muscle pain, and progressive weakness. TIO has been associated with increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) usually by mesenchymal tumors of soft tissue or bone (Phosphaturic Mesenchymal Tumors-PMTs). In rare cases TIO may be observed in association with other malignancies. We report the case of a 66-year-old woman with an occasional diagnosis of both a PMT and an ovarian cancer during the evaluation of TIO. We also systematically review the literature to discover possible correlations between osteomalacia, FGF23 production, and ovarian cancer. Four studies were eligible for the analysis. Two case reports described an association between TIO development and ovarian cancer, whereas the two case-control studies hypothesized a possible correlation between FGF/FGF receptor axis and cancer development. Although it does not provide conclusive evidence regarding the association between TIO and ovarian cancer, this case report highlights the possibility that in the diagnostic workup of suspected TIO, both FGF23-secreting tumors distinct from PMT and tumors unrelated to the clinical presentation of TIO could be identified. This information is important for guiding successful tumor staging and determining the necessity for surgical intervention and/or eventual adjuvant therapy.

Quantitative 1H Magnetic Resonance Imaging on Normal and Pathologic Rat Bones by Solid-State 1H ZTE Sequence with Water and Fat Suppression.

BACKGROUND: Osteoporosis (OP) and osteomalacia (OM) are metabolic bone diseases characterized by mineral and matrix density changes. Quantitative bone matrix density differentiates OM from OP. MRI is a noninvasive and nonionizing imaging technique that can measure bone matrix density quantitatively in ex vivo and in vivo. PURPOSE: To demonstrate water + fat suppressed 1H MRI to compute bone matrix density in ex vivo rat femurs in the preclinical model. STUDY TYPE: Prospective. ANIMAL MODEL: Fifteen skeletally mature female Sprague-Dawley rats, five per group (normal, ovariectomized (OVX), partially nephrectomized/vitamin D (Vit-D) deficient), 250-275 g, ∼15 weeks old. FIELD STRENGTH/SEQUENCE: 7T, zero echo time sequence with water + fat (VAPOR) suppression capability, µCT imaging, and gravimetric measurements. ASSESSMENT: Cortical and trabecular bone segments from normal and disease models were scanned in the same coil along with a dual calibration phantom for quantitative assessment of bone matrix density. STATISTICAL TESTS: ANOVA and linear regression were used for data analysis, with P-values <0.05 statistically significant. RESULTS: The MRI-derived three-density PEG pellet densities have a strong linear relationship with physical density measures (r2 = 0.99). The Vit-D group had the lowest bone matrix density for cortical bone (0.47 ± 0.16 g cm-3), whereas the OVX had the lowest bone matrix density for trabecular bone (0.26 ± 0.04 g cm-3). Gravimetry results confirmed these MRI-based observations for Vit-D cortical (0.51 ± 0.07 g cm-3) and OVX trabecular (0.26 ± 0.03 g cm-3) bone groups. DATA CONCLUSION: Rat femur images were obtained using a modified pulse sequence and a custom-designed double-tuned (1H/31P) transmit-receive solenoid-coil on a 7T preclinical MRI scanner. Phantom experiments confirmed a strong linear relation between MRI-derived and physical density measures and quantitative bone matrix densities in rat femurs from normal, OVX, and Vit-D deficient/partially nephrectomized animals were computed. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Histomorphometric analysis of patients with femoral neck fracture and 25-hydroxyvitamin D deficiency: a cross-sectional study.

INTRODUCTION: Vitamin D deficiency causes osteoporosis, bone mineralization disorders, and osteomalacia. Osteomalacia is diagnosed using blood biochemical tests, clinical symptoms, and imaging; however, accurate detection of mineralization disorders requires tissue observation. We investigated the prevalence of bone mineralization disorders and their relationship with serum 25-hydroxyvitamin D (25OHD) levels in patients with untreated osteoporosis with femoral neck fractures. MATERIALS AND METHODS: A non-demineralized specimen was prepared from the femoral head removed during surgery in 65 patients. Bone histomorphometry of cancerous bone in the femoral head center was conducted. Osteoid volume per bone volume (OV/BV) and osteoid thickness (O.Th) were measured as indicators of mineralization disorder. RESULTS: The mean serum 25OHD level (11.9 ± 5.7 ng/mL) was in the deficiency range (< 12 ng/mL). There were no clinically diagnosed cases of osteomalacia (OV/BV > 10% and O.Th > 12.5 µm); however, one case of mineralization disorder, considered histologically pre-osteomalacia (OV/BV > 5% and O.Th < 12.5 µm), was observed (OB/BV, 17.6%; O.Th, 12.3 µm). Excluding this case, those with severe (25OHD < 12 ng/mL, at risk of osteomalacia; n = 39) and non-severe deficiency (25OHD ≥ 12 ng/mL; n = 25) did not significantly differ in OV/BV (%; 0.77 ± 0.54 vs. 0.69 ± 0.38, p = 0.484) or O.Th (µm; 5.32 ± 1.04 vs. 5.13 ± 0.78, p = 0.410). Further, 25OHD and OV/BV were not significantly correlated (R = - 0.124, p = 0.327). CONCLUSION: This is the first study in the twenty-first century to examine serum 25OHD concentrations and bone mineralization disorders in Japanese patients with osteoporosis. The results indicate that vitamin D deficiency does not necessarily cause bone mineralization disorders and rarely leads to osteomalacia.

Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes.

OBJECTIVES: Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2 h after the first void (TmP/GFR 2 h). The purpose of this study was to evaluate if TmP/GFR calculated from 24 h urine collection (TmP/GFR 24 h) can be used as an alternative for TmP/GFR 2 h in patients with urine phosphate wasting. METHODS: We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24 h and TmP/GFR 2 h. RESULTS: Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2 h (0.35 mmol/L, IQR 0.24-0.47 mmol/L) and TmP/GFR 24 h (0.31 mmol/L, IQR 0.22-0.43 mmol/L). The concordance correlation coefficient between TmP/GFR 2 h and TmP/GFR 24 h was 0.86 (95 % CI: 0.69-0.93), with a systematic bias of 0.05 mmol/L (95 % limits of agreement: -0.10 to 0.20). Furthermore, in 70 % (i.e., 14 patients out of 20) and 80 % (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2 h and TmP/GFR 24 h was within ±30 % and ±35 %, respectively. CONCLUSIONS: Despite TmP/GFR 2 and 24 h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.

Extended curettage for tumour-induced osteomalacia in the bone.

BACKGROUND: extended curettage is generally used to treat infiltrative bone tumours. However, the extent of the curettage performed in previous studies remains unclear. This study aimed to investigate the efficacy of extended curettage for bone tumour-induced osteomalacia. METHODS: we included 12 patients with tumour-induced osteomalacia who underwent extended curettage at our hospital between 2000 and 2022. Extended curettage was applied in cases where tumour resection could cause functional impairment or necessitate complex reconstruction. We investigated patients' clinical and oncological outcomes. RESULTS: patients had a mean age of 55 (24-81) years, and the median follow-up duration after surgery was 3.9 (1.0-14.0) years. The causative tumours were located in the pelvis and lumbar spine. Imaging revealed the tumours to be of the sclerotic, intertrabecular, lytic and mixed types. Intraoperative 3D fluoroscopy was used in 10 patients. Extended curettage with high-speed burring and adjuvant therapy with cauterization using an electric scalpel and ethanol resulted in a remission rate of 83%; no recurrence or metastasis was observed in cases of early postoperative biochemical remission. In cases where the causative tumour was at the lumbar spine and ischium close to the acetabulum, no postoperative biochemical remission was observed, and conservative treatment was continued. Except for one patient with a tumour in the lumbar spine, all patients could walk without a cane. CONCLUSIONS: extended curettage for bone tumour-induced osteomalacia is oncologically and functionally favourable, especially in cases where resection of the causative tumour could cause functional impairment or necessitate complex reconstruction.

Phosphaturic mesenchymal tumor: two cases highlighting differences in clinical and radiologic presentation.

Phosphaturic mesenchymal tumors are rare, usually benign neoplasms that occur in the soft tissue or bone and are the cause of nearly all cases of tumor-induced osteomalacia. Tumor-induced osteomalacia due to phosphaturic mesenchymal tumor is a challenging diagnosis to make-patients present with variable clinical and radiologic findings and the culprit neoplasm is often small and can occur anywhere head to toe. We present two cases of phosphaturic mesenchymal tumor in the scapular body and plantar foot. In both cases, the patient endured years of debilitating symptoms before a tissue diagnosis was eventually reached. Descriptions of clinical presentation, laboratory workup, surgical resection, and imaging characteristics, with a focus on CT, MRI, and functional imaging, are provided to assist with the diagnosis and management of this rare entity. A brief review of current literature and discussion of the differential diagnoses of phosphaturic mesenchymal tumor is also provided.

The Intricacies of Renal Phosphate Reabsorption-An Overview.

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.

Mutations of family with sequence similarity 20-member C gene causing lethal and nonlethal Raine syndrome causes hypophosphatemia rickets.

Family with sequence similarity 20-member C (FAM20C) is a kinase specific to most of the secreted phosphoproteome. FAM20C has been identified as the causative gene of Raine syndrome, initially characterized by lethal osteosclerosis bone dysplasia. However, since the identification of the cases of nonlethal Raine syndrome characterized by hypophosphatemia rickets, the previous definition of Raine syndrome has become debatable and raised a question about the role of mutations of FAM20C in controversial skeletal manifestation in the two forms of the disease. In this study, we aimed to investigate the influence of FAM20C mutations on skeletogenesis. We developed transgenic mice expressing Fam20c mutations mimicking those associated with human lethal and nonlethal Raine syndrome. The results revealed that transgenic mice expressing the mutant Fam20c found in the lethal (KO;G374R) and nonlethal (KO;D446N) Raine syndrome exhibited osteomalacia without osteosclerotic features. Additionally, both mutants significantly increased the expression of the Fgf23, indicating that Fam20c deficiency in skeletal compartments causes hypophosphatemia rickets. Furthermore, as FAM20C kinase activity catalyzes the phosphorylation of secreted proteomes other than those in the skeletal system, global FAM20C deficiency may trigger alterations in other systems resulting in osteosclerosis secondary to hypophosphatemia rickets. Together, the findings of this study suggest that FAM20C deficiency primarily causes hypophosphatemia rickets or osteomalacia; however, the heterogeneous skeletal manifestation in Raine syndrome was not determined solely by specific mutations of FAM20C. The findings also implicated that rickets or osteomalacia caused by FAM20C deficiency would deteriorate into osteosclerosis by the defects from other systems or environmental impacts.

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

RNA Sequencing Reveals Novel Oncogenic Fusions and Depicts Detailed Fusion Transcripts of FN1-FGFR1 in Phosphaturic Mesenchymal Tumors.

Phosphaturic mesenchymal tumors (PMTs) are rare neoplasms of soft tissue or bone. Although previous studies revealed that approximately 50% of PMTs harbor FN1::FGFR1 fusions, the molecular mechanisms in the remaining cases are largely unknown. In this study, fusion genes were investigated using RNA-based next-generation sequencing in 76 retrospectively collected PMTs. Novel fusions were validated with Sanger sequencing and fluorescence in situ hybridization. Fusion genes were detected in 52/76 (68.4%) PMTs, and 43/76 (56.6%) harbored FN1::FGFR1 fusions. Fusion transcripts and breakpoints of the FN1::FGFR1 fusions were diverse. The most common fusion transcript was between exon 20 of FN1 and exon 9 of FGFR1 (7/43, 16.3%). The most upstream breakpoint of the FN1 gene was located at the 3' end of exon 12, and the most downstream breakpoint of the FGFR1 gene was at the 5' end of exon 9, suggesting the inessential nature of the third fibronectin-type domain of FN1 and the necessity of the transmembrane domain of FGFR1 in the FN1::FGFR1 fusion protein, respectively. Moreover, the reciprocal FGFR1::FN1 fusions, which had not been identified in previous studies, were detected in 18.6% (8/43) of FN1::FGFR1 fusion-positive PMTs. Novel fusions were identified in 6/76 (7.9%) FN1::FGFR1 fusion-negative PMTs, including 2 involving FGFR: FGFR1::USP33 (1/76, 1.3%) and FGFR1::TLN1 (1/76, 1.3%). Other novel fusions identified were the PDGFRA::USP35 (1/76, 1.3%), SPTBN1::YWHAQ (1/76, 1.3%), GTF2I::RALGPS1 (1/76, 1.3%), and LTBP1::VWA8 (1/76, 1.3%) fusions. In addition to these novel fusions, FN1::FGFR2 (1/76, 1.3%), NIPBL::BEND2 (1/76, 1.3%), and KIAA1549::BRAF fusions (1/76, 1.3%) were also identified in FN1::FGFR1-negative cases arising from the thigh, ilium, and acetabulum, respectively. The frequency of oncogenic fusions was significantly higher (P = .012) in tumors derived from extremities (29/35, 82.9%) compared with other locations (23/41, 56.1%). No significant correlation was identified between fusions and recurrence (P = .786). In conclusion, we report fusion transcripts and breakpoints of FN1::FGFR1 in PMTs in detail, providing insights into fusion protein functions. We also revealed that a considerable proportion of PMTs without FN1::FGFR1 fusion carried novel fusions, providing further insight into the genetic basis of PMTs.

The effect of burosumab on intact and C-terminal FGF23 measurements.

OBJECTIVE: To investigate the effect of CRYSVITA® (burosumab-twza) on FGF23 measurements in an intact and a C-terminal immunoassay. METHODS: An intact serum FGF23 (MedFrontier) and a C-terminal plasma FGF23 assay (Immutopics) were used. Serum/plasma pools were spiked to span the burosumab therapeutic range (1.4-11.3 µg/ml) and FGF23 recovery was assessed. Patient serum and plasma samples obtained pre and post-burosumab treatment were evaluated on both assays and compared with corresponding phosphorus measurements RESULTS: Spiking burosumab (1.4-11.3 µg/ml) into sample pools resulted in a dose-dependent negative analytical interference on intact FGF23 measurements and no significant interference for C-terminal FGF23 measurements. However, more than a 500-fold median increase (post- vs. pre-burosumab administration) in in vivo FGF23 concentrations were observed by both assays. CONCLUSIONS: Therapeutic concentrations of burosumab result in a negative analytical interference of the intact, but not the C-terminal FGF23 immunoassay. Despite this in vitro analytical interference in the intact assay, relatively large elevations of both intact FGF23 and C-terminal FGF23 measurements were observed in vivo following burosumab administration. Following burosumab administration, FGF23 measurements must be interpreted within the clinical context of the patient and other relevant biomarker results. SUMMARY: This article describes a negative analytical interference by burosumab in an intact FGF23 immunoassay. The recovery of C-terminal FGF23 is not significantly affected by the presence of burosumab. In vivo, both assays demonstrate extreme FGF23 elevations in the presence of the drug. Furthermore, the measurement of FGF23 blocked by burosumab is not clinically useful regarding hypophosphataemia.

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.

Diagnostic Approach to Patients with Low Serum Alkaline Phosphatase.

Increased serum levels of alkaline phosphatase (ALP) are widely recognized as a biochemical marker of many disorders affecting the liver or bone. However, the approach for patients with low ALP phosphatase is not well-established. Low serum ALP is an epiphenomenon of many severe acute injuries and diseases. Persistently low serum ALP may be secondary to drug therapy (including antiresorptives) or a variety of acquired disorders, such as malnutrition, vitamin and mineral deficiencies, endocrine disorders, etc. Hypophosphatasia, due to pathogenic variants of the ALPL gene, which encodes tissue non-specific ALP, is the most common genetic cause of low serum ALP. Marked bone hypomineralization is frequent in severe pediatric-onset cases. However, adult forms of hypophosphatasia usually present with milder manifestations, such as skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems, and stress fractures. The diagnostic approach to these patients is discussed. Measuring several ALP substrates, such as pyrophosphate, pyridoxal phosphate, or phosphoethanolamine, may help to establish enzyme deficiency. Gene analysis showing a pathogenic variant in ALPL may confirm the diagnosis. However, a substantial proportion of patients show normal results after sequencing ALPL exons. It is still unknown if those patients carry unidentified mutations in regulatory regions of ALPL, epigenetic changes, or abnormalities in other genes.

Osteomalacia Prevalence, Biochemical Profile, and Histology in Patients with Low-Energy Hip Fractures Over the Age of 45.

Our objective was to determine the prevalence of osteomalacia in low-energy hip fracture patients over the age of 45, based on biochemical and histological measures. This cross-sectional study included 72 patients over 45 with low-energy mechanism hip fractures. Samples of fasting venous blood were taken for hemograms and serum biochemistry analyses. Bicortical biopsies of the iliac crest were obtained, processed, and evaluated by an expert pathologist for osteomalacia. Biochemical osteomalacia (b-OM) is defined according to a distinct criterion. A low level of serum calcium, phosphorus, albumin, and 25OHD was found in 43.1, 16.7, 73.6, and 59.7% of patients, respectively. 50.0% of patients had high serum alkaline phosphatase (ALP) levels. b-OM was found in 30 (41.7%), and no significant association was found with PTH, Cr, Alb, age, sex, fracture type, side of the trauma, and season were not associated with osteomalacia. Osteomalacia was diagnosed on histopathological analysis in 19/72 (26.7%), and 54/72 (75.0%) of all cases fulfilled b-OM criteria. In the histologic evaluation, osteoid seam width, osteoid surface, and osteoid volume were 28.5 µm, 25.6, and 12.1%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the biochemical test for detecting osteomalacia were 73.6, 64.2, 42.4, 87.2, and 66.7%, respectively. Up to 30% of elderly patients with low-energy hip fractures are affected by osteomalacia. A biochemical screening along with a bone biopsy and histopathologic evaluation may be logical in a high-risk population for osteomalacia diagnosis.

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.

Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders.

OBJECTIVE: Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions. METHODS: Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported. RESULTS: iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001). CONCLUSIONS: This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.