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The SUNFLOWER study was initiated in Japan and South Korea to clarify the course of X-linked hypophosphatemic rickets/osteomalacia (XLH); delineate its physical, mental, and financial burdens; and collect information on treatment. Here, we report cross-sectional data at the time of patient enrollment to better understand the real-world management and complications in patients with XLH and examine the effect of XLH on quality of life (QOL). This is an ongoing, longitudinal, observational cohort study of patients with a diagnosis of XLH. Data from 147 patients (118 in Japan and 29 in South Korea) were evaluated. In total, 77 children (mean age, 9.7 yr; 67.5% female) and 70 adults (mean age, 37.6 yr; 65.7% female) were enrolled. PHEX gene mutations were confirmed in 46/77 (59.7%) children and 37/70 (52.9%) adults. Most patients in both age groups were receiving a combination of phosphate and active vitamin D at baseline. The mean height Z-score was −2.21 among adults (male: −2.34; female: −2.14). The mean Rickets Severity Score in children was 1.62. Whereas children appeared to have low pain levels (mean revised faces pain scale score, 1.3), adults reported mild-to-moderate pain (mean Brief Pain Inventory pain severity, 2.02). Mean QOL in children (assessed using the 10-item short-form health survey for children) was low, with a score below normative level for physical functioning. In adults, results from the Western Ontario and McMaster Universities osteoarthritis index indicated the presence of pain, stiffness, and decreased physical function. The respective mean total days/year of work/school non-attendance due to symptoms/complications and management of XLH were 0.7 and 3.0 among adults, and 6.4 and 6.1 among children. Our findings reconfirmed a relationship between disease and QOL in patients with XLH. We anticipate that these data will be important in enabling clinicians to understand the daily reality of patients with XLH. Lay Summary: X-linked hypophosphatemic rickets/osteomalacia (XLH) is a rare, PHEX gene mutation-linked disorder that causes weak bones and bone deformities. The ongoing SUNFLOWER study aims to collect information on Japanese and South Korean patients with XLH to better understand how this disease progresses over time, its impact on quality of life (QOL), and how it is currently being treated. Data from 147 patients (77 children and 70 adults) were evaluated. Over half of the adults and children included in this study had a confirmed PHEX gene mutation. Although most patients were receiving conventional therapy for XLH, laboratory tests revealed that they had underlying issues with bone health and that their growth rates were still being negatively affected. Bone-related complications were more common among adults than children. Children reported low levels of pain, whereas adults reported mild-to-moderate pain. Children with XLH scored low for physical functioning on QOL tests. Adults with XLH reported pain, stiffness, and decreased physical function on QOL tests. XLH had a larger impact on children's school attendance than adults' work attendance. Our findings will help improve understanding of the daily reality of XLH patients in Japan and South Korea. [ABSTRACT FROM AUTHOR]

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced bone morphogenetic protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of growth/differentiation factor 5 (Gdf5) is enhanced in Hyp entheses at P14. Thus, to determine a role for GDF5 in enthesopathy development, Gdf5 was deleted globally in Hyp mice and conditionally in Scx + cells of Hyp mice. In both murine models, BMP/IHH signaling was similarly decreased in Hyp entheses, leading to decreased enthesopathy. BMP/IHH signaling remained unaffected in WT entheses with decreased Gdf5 expression. Moreover, deletion of Gdf5 in Hyp entheses starting at P30, after enthesopathy has developed, partially reversed enthesopathy. Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy. Lay Summary: X-linked hypophosphatemia (XLH) is a rare bone disorder that leads to short stature and poorly mineralized bones. As adults, patients with XLH often develop a mineralization of the bone-tendon attachment site, called enthesopathy, which results in significant pain. We previously showed that Achilles bone-tendon attachment sites (entheses) in mice with XLH (Hyp) have an enthesopathy characterized by increased bone morphogenetic protein (BMP) signaling. In the current studies, we show that treating Hyp mice with the BMP signaling inhibitor palovarotene prevents enthesopathy, demonstrating that the increased BMP signaling in Hyp entheses leads to enthesopathy development. We also reported that gene expression of Gdf5, which activates BMP signaling, is enhanced in Hyp entheses. Therefore, to determine if the enhanced Gdf5 expression leads to the increased BMP signaling seen Hyp entheses, Gdf5 was deleted from Hyp mice and also deleted specifically in the entheses of Hyp mice. In both mouse models, enthesopathy development was attenuated, demonstrating that the increased Gdf5 expression in Hyp entheses plays a role in enthesopathy development. These data indicate that blocking GDF5 and BMP signaling may prevent enthesopathy in patients with XLH. [ABSTRACT FROM AUTHOR]

Introduction: Tumor-induced osteomalacia (TIO), is a rare acquired paraneoplastic syndrome characterized by defective bone mineralization, caused by the overproduction of fibroblast growth factor 23 (FGF23) by a tumor. Material and methods: We conducted a systematic review to identify all case reports of TIO, focusing on those associated with mesenchymal tumors. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) consensus, and we included patients with a diagnosis of TIO and histological confirmation of phosphaturic mesenchymal tumors or resolution of the condition after treatment of the tumor. Bibliographical searches were carried out until December 2023 in the Cochrane Library, Medline and Embase, as well as congress abstracts online. Results: We identified 769 articles with 1979 cases reported. Most patients were adults, with a higher incidence on men. Disease duration before diagnosis is a mean of 4.8 years. Most tumors were histologically classified as PMT. Lower limbs were the predominant location. Hypophosphatemia was present in 99.8 % of patients. The FGF23 was elevated at diagnosis in 95.5 %. Resection of the tumor was the treatment of choice in most of patients. After resection, there was a clinical improvement in 97.6 % of cases, and serum phosphorus and FGF23 levels returned to normal ranges in 91.5 % and 81.4 % of the patients, respectively. Conclusion: TIO is usually misdiagnosed with rheumatological or musculoskeletal disorders. The diagnosis should be suspected in patients with hypophosphatemic osteomalacia, and the measurement of serum FGF23 can be useful for diagnosis and management.

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue‐nonspecific alkaline phosphatase. Adult‐onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first‐line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64‐year‐old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6‐minute walk test (525 to 606 m). The EQ‐5D‐5L index was also improved (0.757 to 0.895). Within a follow‐up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue‐nonspecific alkaline phosphatase. Adult‐onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first‐line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64‐year‐old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6‐minute walk test (525 to 606 m). The EQ‐5D‐5L index was also improved (0.757 to 0.895). Within a follow‐up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Hypophosphatasia (HPP), caused by loss‐of‐function mutations in the ALPL gene encoding tissue‐nonspecific alkaline phosphatase (TNAP), is characterized by skeletal and dental hypomineralization that can vary in severity from life‐threatening to milder manifestations only in adulthood. PHOSPHO1 deficiency leads to early‐onset scoliosis, osteomalacia, and fractures that mimic pseudo‐HPP. Asfotase alfa, a life‐saving enzyme replacement therapy approved for pediatric‐onset HPP, requires subcutaneous injections 3 to 6 times per week. We recently showed that a single injection of an adeno‐associated virus vector serotype 8 harboring TNAP‐D10 (AAV8‐TNAP‐D10) effectively prevented skeletal disease and prolonged life in Alpl−/− mice phenocopying infantile HPP. Here, we aimed to determine the efficacy of AAV8‐TNAP‐D10 in improving the skeletal and dental phenotype in the AlplPrx1/Prx1 and Phospho1−/− mouse models of late‐onset (adult) HPP and pseudo‐HPP, respectively. A single dose of 3 × 1011 vector genomes per body (vg/b) was injected intramuscularly into 8‐week‐old AlplPrx1/Prx1 and wild‐type (WT) littermates, or into 3‐day‐old Phospho1−/− and WT mice, and treatment efficacy was evaluated after 60 days for late‐onset HPP mice and after 90 days for Phospho1−/− mice. Biochemical analysis showed sustained serum alkaline phosphatase activity and reduced plasma PPi levels, and radiographic images, micro‐computed tomography (micro‐CT) analysis, and hematoxylin and eosin (H&E) staining showed improvements in the long bones in the late‐onset HPP mice and corrected scoliosis in the Phospho1−/− mice. Micro‐CT analysis of the dentoalveolar complex did not reveal significant changes in the phenotype of late‐onset HPP and pseudo‐HPP models. Moreover, alizarin red staining analysis showed that AAV8‐TNAP‐D10 treatment did not promote ectopic calcification of soft organs in adult HPP mice after 60 days of treatment, even after inducing chronic kidney disease. Overall, the AAV8‐TNAP‐D10 treatment improved the skeletal phenotype in both the adult HPP and pseudo‐HPP mouse models. This preclinical study will contribute to the advancement of gene therapy for the improvement of skeletal disease in patients with heritable forms of osteomalacia. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Inactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor‐23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23‐mediated hypophosphatemia, such as X‐linked hypophosphatemia (XLH) and tumor‐induced osteomalacia (TIO), in whom pathology‐driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23‐mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23‐mediated and FGF23‐independent hypophosphatemia and defined cut‐off levels for both intact FGF23 (iFGF23) and C‐terminal FGF23 (cFGF23) that can accurately distinguish between FGF23‐mediated and FGF23‐independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23‐mediated from FGF23‐independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23‐independent hypophosphatemia. There was overlap in the cFGF23 range of 45–90 RU/mL between genetic forms of FGF23 excess and FGF23‐independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23‐mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23‐mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut‐off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

ABSTRACT Inactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The article discusses tumor-induced osteomalacia (TIO), a rare paraneoplastic syndrome caused by tumors that produce Fibroblast Growth Factor-23 (FGF23). Patients with TIO experience symptoms such as weakness, pain, and fractures due to hormonal imbalances and bone deterioration. The article highlights the challenges in diagnosing TIO, as it is often mistaken for osteoporosis. The authors present a study that integrates biochemical and imaging data to differentiate TIO from osteoporosis, potentially avoiding the need for invasive bone biopsies. However, further validation and investigation are needed to confirm the findings and determine if the approach can be applied to other conditions. [Extracted from the article]

Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

ABSTRACT Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age‐specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Objectives: To estimate the prevalence of chondrocalcinosis and calcium pyrophosphate dihydrate deposition disease (CPPD) in patients with low alkaline phosphatase (ALP) levels and a positive ALPL genetic study (+GT) for hypophosphatasia (HPP) compared to those with the same biochemical abnormality and a negative genetic test (-GT). As a secondary objective, to analyze the biochemical factors associated with its presence in subjects with ALPL variants., Methods: Seventy-eight subjects with persistently low ALP levels and ALPL genetic test were included. Baseline and 24-mo knee ultrasounds were performed in 42 + GT and 36 -GT subjects, in whom the fibrocartilage, hyaline cartilage of menisci, tendons, and synovial fluid were scanned to detect calcium pyrophosphate deposits. A MyLabTwice ultrasound machine (Esaote) with a multifrequency linear array transducer (4-13 MHz) was used., Results: A higher percentage of chondrocalcinosis was observed in the +GT group [9/42 (21.4%)] compared to the -GT group [2/36 (5.6%), p =.045)]. Two patients (4.76%), both in the +GT group, had arthritis secondary to CPPD. No new cases were identified at the 24-mo control. When comparing +GT patients with and without chondrocalcinosis, ALP levels were lower, and pyridoxal-5'-phosphate (PLP) and phosphate levels were higher in the former group ( p <.05). Logistic regression analysis revealed that higher PLP levels are associated with the presence of chondrocalcinosis (OR: 1.1; 95% confidence interval, CI, 1.001-1.012)., Conclusions: Chondrocalcinosis was a frequent ultrasonographic finding in HPP. Arthritis secondary to calcium pyrophosphate deposits, however, proved less prevalent. Genetic causes, such as HPP, should be considered when evaluating patients with chondrocalcinosis in clinical practice., Competing Interests: P.A. and C.T. have received fees for advisory board participation from Alexion Pharmaceuticals and have been recipients of a research grant from this biopharmaceutical company, but not for this original manuscript. The rest of authors declare that they do not have any other conflict of interest regarding the publication of this article., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Summary: We report the most comprehensive clinical and molecular characterization of XLH patients performed in Chile. We show high prevalence of musculoskeletal burden and pain, associated with significantly impaired physical capacity and quality of life, with many relevant complications presenting more frequently than previously reported in cohorts from developed countries. Introduction: Our current understanding of the clinical presentation and natural history of X-linked hypophosphatemia (XLH) comes mainly from cohorts from developed countries, with limited data on the clinical and genetic abnormalities of XLH patients in South America. Objective: To describe the clinical, biochemical, and molecular presentation of patients with XLH in Chile. Methods: Patients with XLH referred by endocrinologist throughout Chile were included. Demographic data and clinical presentation were obtained from a clinical interview. Surveys were applied for quality of life (QoL), pain, and functionality. FGF23 was measured by ELISA, and genetic testing was performed. Imaging studies were conducted to assess skeletal and renal involvement. Results: We included 26 patients, aged 2–64 years, from 17 unrelated Chilean families. All pediatric patients but only 40% of adults were receiving conventional therapy, while 65% of all patients had elevated alkaline phosphatase. All patients had mutations in PHEX, including 5 novel variants. Radiographic skeletal events (RSE) and enthesopathies in adults were frequent (34% and 85%, respectively). The duration of treatment was associated with fewer RSE (p < 0.05). Most adults reported pain and impaired QoL, and 50% had impaired physical capacity. The number of enthesopathies was associated with worse pain and stiffness scores (p < 0.05). Conclusion: Chilean patients with XLH have a high prevalence of musculoskeletal burden associated with pain and impaired physical capacity and QoL, especially in adults who were generally undertreated. These data identify a significant unmet need, inform our understanding of the current status of patients, and can guide care for XLH patients in similarly socioeconomically defined countries. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is caused by loss‐of‐function mutations in the ALPL gene that encodes tissue‐nonspecific alkaline phosphatase (TNAP), whose deficiency results in the accumulation of extracellular inorganic pyrophosphate (PPi), a potent mineralization inhibitor. Skeletal and dental hypomineralization characterizes HPP, with disease severity varying from life‐threatening perinatal or infantile forms to milder forms that manifest in adulthood or only affect the dentition. Enzyme replacement therapy (ERT) using mineral‐targeted recombinant TNAP (Strensiq/asfotase alfa) markedly improves the life span, skeletal phenotype, motor function, and quality of life of patients with HPP, though limitations of ERT include frequent injections due to a short elimination half‐life of 2.28 days and injection site reactions. We tested the efficacy of a single intramuscular administration of adeno‐associated virus 8 (AAV8) encoding TNAP‐D10 to increase the life span and improve the skeletal and dentoalveolar phenotypes in TNAP knockout (Alpl−/−) mice, a murine model for severe infantile HPP. Alpl−/− mice received 3 × 1011 vector genomes/body of AAV8‐TNAP‐D10 within 5 days postnatal (dpn). AAV8‐TNAP‐D10 elevated serum ALP activity and suppressed plasma PPi. Treatment extended life span of Alpl−/− mice, and no ectopic calcifications were observed in the kidneys, aorta, coronary arteries, or brain in the 70 dpn observational window. Treated Alpl−/− mice did not show signs of rickets, including bowing of long bones, enlargement of epiphyses, or fractures. Bone microstructure of treated Alpl−/− mice was similar to wild type, with a few persistent small cortical and trabecular defects. Histology showed no measurable osteoid accumulation but reduced bone volume fraction in treated Alpl−/− mice versus controls. Treated Alpl−/− mice featured normal molar and incisor dentoalveolar tissues, with the exceptions of slightly reduced molar enamel and alveolar bone density. Histology showed the presence of cementum and normal periodontal ligament attachment. These results support gene therapy as a promising alternative to ERT for the treatment of HPP. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

In children and adolescents, distinguishing tumor‐induced rickets/osteomalacia (TIR/O) from hereditary hypophosphatemic rickets/osteomalacia (HR/O) is a medical challenge. We retrospectively studied 10 Chinese children and adolescents with TIR/O who underwent surgery at a mean age of 17.4 ± 2.1 years and compared their characteristics to 24 age‐ and sex‐matched patients with X‐linked hypophosphatemia (XLH). Positive family history of HR/O and dental problems, such as enamel hypoplasia and dental abscess, were reported in 8 (33.3%) and 5 (20.8%) patients with XLX, respectively, but not in patients with TIR/O. In addition, in comparison with XLH patients, TIR/O patients had an older disease onset age (150 versus 24 months, p < 0.001), a higher height standard deviation score (SDS; −1.2 ± 1.8 versus −4.0 ± 1.4, p < 0.001), a lower Z‐score of bone mineral density (BMD) at lumbar spine (LS) (−3.9 [6.0] versus +1.8 [7.0], p < 0.001), and a higher serum intact fibroblast growth factor 23 (FGF23) level (500.27 ± 87.20 versus 121.71 ± 70.94 pg/mL, p < 0.001), corresponding to a lower serum phosphate level (0.52 ± 0.07 versus 0.64 ± 0.11 mmol/L, p = 0.005) and a higher serum alkaline phosphatase (ALP) level (557 [631] versus 305 [249] U/L, p = 0.005). We generated receiver operating characteristic (ROC) curves and calculated the area under the ROC curve (AUC). The AUCs of onset age, FGF23, and LS Z‐score were equal to 1, suggesting that these are excellent indices for the differential diagnosis between TIR/O and XLH. In summary, our study furthers our understanding of the spectrum of clinical, biochemical, and pathologic findings associated with TIR/O. For children and adolescent patients with HR/O, a comprehensive and careful clinical and laboratory evaluation is of great importance, and we recommend enquiry of the family history, onset age, and dental problems, as well as measurement of serum FGF23 and BMD. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss‐of‐function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal‐recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ‐701, a human ENPP1‐Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ‐701 were investigated in Enpp1asj/asj mice, a murine model of ENPP1 deficiency. Enpp1asj/asj mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild‐type (WT) mice. Enpp1asj/asj mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1asj/asj mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ‐701. Treatment of ENPP1‐deficient mice every other day with INZ‐701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1asj/asj mice, demonstrating the potential of INZ‐701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

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.. [ABSTRACT FROM AUTHOR]

ABSTRACT Tumor‐induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte‐derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45‐year‐old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44–215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate‐regulating endopeptidase homolog, X‐linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Genetically modified mice have provided novel insights into the mechanisms of activation and inactivation of vitamin D, and in the process have provided phenocopies of acquired human disease such as rickets and osteomalacia and inherited diseases such as pseudovitamin D deficiency rickets, hereditary vitamin D resistant rickets, and idiopathic infantile hypercalcemia. Both global and tissue‐specific deletion studies leading to decreases of the active form of vitamin D, calcitriol [1,25(OH)2D], and/or of the vitamin D receptor (VDR), have demonstrated the primary role of calcitriol and VDR in bone, cartilage and tooth development and in the regulation of mineral metabolism and of parathyroid hormone (PTH) and FGF23, which modulate calcium and phosphate fluxes. They have also, however, extended the spectrum of actions of calcitriol and the VDR to include, among others: modulation, jointly and independently, of skin metabolism; joint regulation of adipose tissue metabolism; cardiovascular function; and immune function. Genetic studies in older mice have also shed light on the molecular mechanisms underlying the important role of the calcitriol/VDR pathway in diseases of aging such as osteoporosis and cancer. In the course of these studies in diverse tissues, important upstream and downstream, often tissue‐selective, pathways have been illuminated, and intracrine, as well as endocrine actions have been described. Human studies to date have focused on acquired or genetic deficiencies of the prohormone vitamin D or the (generally inactive) precursor metabolite 25‐hyrodxyvitamin D, but have yet to probe the pleiotropic aspects of deficiency of the active form of vitamin D, calcitriol, in human disease. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Tumor‐induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte‐derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45‐year‐old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44–215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate‐regulating endopeptidase homolog, X‐linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

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).. [ABSTRACT FROM AUTHOR]

Genetically modified mice have provided novel insights into the mechanisms of activation and inactivation of vitamin D, and in the process have provided phenocopies of acquired human disease such as rickets and osteomalacia and inherited diseases such as pseudovitamin D deficiency rickets, hereditary vitamin D resistant rickets, and idiopathic infantile hypercalcemia. Both global and tissue‐specific deletion studies leading to decreases of the active form of vitamin D, calcitriol [1,25(OH)2D], and/or of the vitamin D receptor (VDR), have demonstrated the primary role of calcitriol and VDR in bone, cartilage and tooth development and in the regulation of mineral metabolism and of parathyroid hormone (PTH) and FGF23, which modulate calcium and phosphate fluxes. They have also, however, extended the spectrum of actions of calcitriol and the VDR to include, among others: modulation, jointly and independently, of skin metabolism; joint regulation of adipose tissue metabolism; cardiovascular function; and immune function. Genetic studies in older mice have also shed light on the molecular mechanisms underlying the important role of the calcitriol/VDR pathway in diseases of aging such as osteoporosis and cancer. In the course of these studies in diverse tissues, important upstream and downstream, often tissue‐selective, pathways have been illuminated, and intracrine, as well as endocrine actions have been described. Human studies to date have focused on acquired or genetic deficiencies of the prohormone vitamin D or the (generally inactive) precursor metabolite 25‐hyrodxyvitamin D, but have yet to probe the pleiotropic aspects of deficiency of the active form of vitamin D, calcitriol, in human disease. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Introduction: Tumor-induced osteomalacia (TIO), is a rare acquired paraneoplastic syndrome characterized by defective bone mineralization, caused by the overproduction of fibroblast growth factor 23 (FGF23) by a tumor., Material and Methods: We conducted a systematic review to identify all case reports of TIO, focusing on those associated with mesenchymal tumors. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) consensus, and we included patients with a diagnosis of TIO and histological confirmation of phosphaturic mesenchymal tumors or resolution of the condition after treatment of the tumor. Bibliographical searches were carried out until December 2023 in the Cochrane Library, Medline and Embase, as well as congress abstracts online., Results: We identified 769 articles with 1979 cases reported. Most patients were adults, with a higher incidence on men. Disease duration before diagnosis is a mean of 4.8 years. Most tumors were histologically classified as PMT. Lower limbs were the predominant location. Hypophosphatemia was present in 99.8 % of patients. The FGF23 was elevated at diagnosis in 95.5 %. Resection of the tumor was the treatment of choice in most of patients. After resection, there was a clinical improvement in 97.6 % of cases, and serum phosphorus and FGF23 levels returned to normal ranges in 91.5 % and 81.4 % of the patients, respectively., Conclusion: TIO is usually misdiagnosed with rheumatological or musculoskeletal disorders. The diagnosis should be suspected in patients with hypophosphatemic osteomalacia, and the measurement of serum FGF23 can be useful for diagnosis and management., Competing Interests: None of the authors has conflicts of interest., (© 2024 The Authors. Published by Elsevier Inc.)

ABSTRACT We describe two women with a misdiagnosed fracturing bone disease who were treated erroneously with i.v. zoledronate. Over the next year, they suffered marked clinical and radiographic deterioration in skeletal disease. Both were eventually diagnosed with hypophosphatemic osteomalacia secondary to acquired Fanconi syndrome (caused by light‐chain myeloma in one case and tenofovir treatment in the other). Appropriate treatment with phosphate supplementation was instituted with clinical improvement. These cases illustrate the importance of not missing osteomalacia in adults presenting with fractures, and the potentially damaging effects of treatment with long‐acting inhibitors of bone resorption in these circumstances. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

PHEX is predominantly expressed by bone and tooth‐forming cells, and its inactivating mutations in X‐linked hypophosphatemia (XLH) lead to renal phosphate wasting and severe hypomineralization of bones and teeth. Also present in XLH are hallmark hypomineralized periosteocytic lesions (POLs, halos) that persist despite stable correction of serum phosphate (Pi) that improves bulk bone mineralization. In XLH, mineralization‐inhibiting osteopontin (OPN, a substrate for PHEX) accumulates in the extracellular matrix of bone. To investigate how OPN functions in Hyp mice (a model for XLH), double‐null (Hyp;Opn−/−) mice were generated. Undecalcified histomorphometry performed on lumbar vertebrae revealed that Hyp;Opn−/− mice had significantly reduced osteoid area/bone area (OV/BV) and osteoid thickness of trabecular bone as compared to Hyp mice, despite being as hypophosphatemic as Hyp littermate controls. However, tibias examined by synchrotron radiation micro‐CT showed that mineral lacunar volumes remained abnormally enlarged in these double‐null mice. When Hyp;Opn−/− mice were fed a high‐Pi diet, serum Pi concentration increased, and OV/BV and osteoid thickness normalized, yet mineral lacunar area remained abnormally enlarged. Enpp1 and Ankh gene expression were increased in double‐null mice fed a high‐Pi diet, potentially indicating a role for elevated inhibitory pyrophosphate (PPi) in the absence of OPN. To further investigate the persistence of POLs in Hyp mice despite stable correction of serum Pi, immunohistochemistry for OPN on Hyp mice fed a high‐Pi diet showed elevated OPN in the osteocyte pericellular lacunar matrix as compared to Hyp mice fed a control diet. This suggests that POLs persisting in Hyp mice despite correction of serum Pi may be attributable to the well‐known upregulation of mineralization‐inhibiting OPN by Pi, and its accumulation in the osteocyte pericellular matrix. This study shows that OPN contributes to osteomalacia in Hyp mice, and that genetic ablation of OPN in Hyp mice improves the mineralization phenotype independent of systemic Pi‐regulating factors. © 2020 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

We describe two women with a misdiagnosed fracturing bone disease who were treated erroneously with i.v. zoledronate. Over the next year, they suffered marked clinical and radiographic deterioration in skeletal disease. Both were eventually diagnosed with hypophosphatemic osteomalacia secondary to acquired Fanconi syndrome (caused by light‐chain myeloma in one case and tenofovir treatment in the other). Appropriate treatment with phosphate supplementation was instituted with clinical improvement. These cases illustrate the importance of not missing osteomalacia in adults presenting with fractures, and the potentially damaging effects of treatment with long‐acting inhibitors of bone resorption in these circumstances. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z‐score < −2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next‐generation sequencing revealed heterozygous loss‐of‐function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild‐type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten‐week‐old male Enpp1asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro‐CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Fibrous dysplasia (FD) is a mosaic disorder of benign fibro‐osseous lesions, which may be associated with extraskeletal features as part of McCune‐Albright syndrome (MAS). Cranial base abnormalities, including Chiari I malformation (CM1), in which the cerebellum extends below the foramen magnum, and secondary basilar invagination (BI), in which the odontoid prolapses into the posterior cranial fossa, are potentially serious complications of metabolic bone disorders. The purpose of this study was to determine the prevalence, natural history, and risk factors for CM1 and BI in patients with FD/MAS, and to determine mechanisms of cranial base deformities. Clinical and radiographic data from subjects in an FD/MAS natural history study were evaluated and compared to normal controls. In 158 patients with craniofacial FD, 10 (6.3%) cases of CM1 and 12 (7.6%) cases of BI were diagnosed. No cranial base abnormalities were identified in 10 control subjects. Craniomorphometric and volumetric analyses identified cranial constriction and cranial settling as the primary mechanisms of cranial base abnormalities, whereas intracranial hypertension was a contributing factor in a minority of subjects. Longitudinal analyses found progression of odontoid position with age, but no progression of tonsillar position. No endocrinopathies were associated with CM1. MAS endocrinopathies associated with BI included hyperthyroidism (odds ratio [OR] 12.0; 95% confidence interval [CI], 2.9 to 55.6; p < 0.01), precocious puberty (OR 5.6; 95% CI, 1.2 to 26.0; p < 0.05), and hypophosphatemia (OR 7.7; 95% CI, 1.9 to 27.0; p < 0.01). Scoliosis was associated with both CM1 (OR 4.8; 95% CI, 1.1 to 22.8; p < 0.05) and BI (OR = infinity; 95% CI, 4.7 to infinity; p < 0.01). This study successfully characterized cranial base abnormalities in FD/MAS and the pathophysiological connection between them. These findings support routine screening for cranial base abnormalities in patients with craniofacial FD, as well as aggressive management of contributory risk factors. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present in the first year of life with renal Fanconi syndrome that evolves to progressive chronic kidney disease (CKD). Despite the multiple risk factors for bone disease, the frequency and severity of skeletal disorders in nephropathic cystinosis have not been described. We performed systematic bone and mineral evaluations of subjects with cystinosis seen at the NIH (n = 30), including history and physical examination, serum and urine biochemistries, DXA, vertebral fracture assessment, skeletal radiographs, and renal ultrasound. Additionally, histomorphometric analyses are reported on six subjects seen at the UCLA Bone and Mineral Metabolism Clinic. In NIH subjects, mean age was 20 years (range, 5 to 44 years), 60% were CKD stages G1 to G4, and 40% had a renal transplant. Mean bone mineral density (BMD) Z‐scores were decreased in the femoral neck, total hip, and 1/3 radius (p < 0.05). Low bone mass at one or more sites was present in 46% of subjects. Twenty‐seven percent of subjects reported one or more long bone fractures. Thirty‐two percent of subjects had incidental vertebral fractures, which were unrelated to transplant status. Long‐bone deformity/bowing was present in 64%; 50% had scoliosis. Diffuse osteosclerosis was present in 21% of evaluated subjects. Risk factors included CKD, phosphate wasting, hypercalciuria, secondary hyperparathyroidism, hypovitaminosis D, male hypogonadism, metabolic acidosis, and glucocorticoid/immunosuppressive therapy. Sixty‐one percent of the non‐transplanted subjects had ultrasonographic evidence of nephrocalcinosis or nephrolithiasis. Histomorphometric analyses showed impaired mineralization in four of six studied subjects. We conclude that skeletal deformities, decreased bone mass, and vertebral fractures are common and relevant complications of nephropathic cystinosis, even before renal transplantation. Efforts to minimize risk factors for skeletal disease include optimizing mineral metabolism and hormonal status, combined with monitoring for nephrocalcinosis/nephrolithiasis. © 2018 This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

ABSTRACT: Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high‐resolution peripheral quantitative computed tomography (HR‐pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (µCT) at 19‐micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D–replete premenopausal women, 77 postmenopausal women, and in a 27‐year‐old woman with vitamin D–dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR‐pQCT and µCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r2 = 0.5 and –0.4, respectively) and correlated inversely in pre‐ and postmenopausal women (both r2 = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post‐ than in premenopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5, respectively; MMD 65.4% ± 1.8 versus 66.6% ± 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z‐scores femoral neck –4.3 SD, lumbar spine –3.8 SD). Low‐radiation HR‐pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT: Osteocytes remodel their surrounding perilacunar matrix and canalicular network to maintain skeletal homeostasis. Perilacunar/canalicular remodeling is also thought to play a role in determining bone quality. X‐linked hypophosphatemia (XLH) is characterized by elevated serum fibroblast growth factor 23 (FGF23) levels, resulting in hypophosphatemia and decreased production of 1,25 dihydroxyvitamin D (1,25D). In addition to rickets and osteomalacia, long bones from mice with XLH (Hyp) have impaired whole‐bone biomechanical integrity accompanied by increased osteocyte apoptosis. To address whether perilacunar/canalicular remodeling is altered in Hyp mice, histomorphometric analyses of tibia and 3D intravital microscopic analyses of calvaria were performed. These studies demonstrate that Hyp mice have larger osteocyte lacunae in both the tibia and calvaria, accompanied by enhanced osteocyte mRNA and protein expression of matrix metalloproteinase 13 (MMP13) and genes classically used by osteoclasts to resorb bone, such as cathepsin K (CTSK). Hyp mice also exhibit impaired canalicular organization, with a decrease in number and branching of canaliculi extending from tibial and calvarial lacunae. To determine whether improving mineral ion and hormone homeostasis attenuates the lacunocanalicular phenotype, Hyp mice were treated with 1,25D or FGF23 blocking antibody (FGF23Ab). Both therapies were shown to decrease osteocyte lacunar size and to improve canalicular organization in tibia and calvaria. 1,25D treatment of Hyp mice normalizes osteocyte expression of MMP13 and classic osteoclast markers, while FGF23Ab decreases expression of MMP13 and selected osteoclast markers. Taken together, these studies point to regulation of perilacunar/canalicular remodeling by physiologic stimuli including hypophosphatemia and 1,25D. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which unregulated hypersecretion of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMT) causes renal phosphate wasting, hypophosphatemia, and osteomalacia. The resulting mineral homeostasis abnormalities and skeletal manifestations can be reversed with surgical resection of the tumor. Unfortunately, PMTs are often difficult to locate, and medical treatment with oral phosphate and vitamin D analogues is either insufficient to manage the disease or not tolerated. Octreotide has been proposed as a potential treatment for TIO due to the presence of somatostatin receptors (SSTR) on PMTs; however, the role of somatostatin signaling in PMTs and the efficacy of treatment of TIOs with somatostatin analogues is not clear. In an effort to evaluate the efficacy of octreotide therapy in TIO, five subjects with TIO were treated with octreotide for 3 days. Blood intact FGF23, phosphate, and 1,25(OH)2D3, and tubular reabsorption of phosphate (TRP) were measured at frequent time points during treatment. Octreotide's effects were assessed by comparing group means of the biochemical parameters at each time-point to mean baseline values. There were no significant changes in blood phosphate, FGF23, 1,25(OH)2D3, or TRP during octreotide treatment, consistent with a lack of efficacy of octreotide in treating TIO. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires α-Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses α-Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of α-Klotho in the feto-maternal interface of both mouse and human normal-term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild-type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20-fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD-24-hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti-FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25-hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP), caused by loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNAP), is characterized by skeletal and dental hypomineralization that can vary in severity from life-threatening to milder manifestations only in adulthood. PHOSPHO1 deficiency leads to early-onset scoliosis, osteomalacia, and fractures that mimic pseudo-HPP. Asfotase alfa, a life-saving enzyme replacement therapy approved for pediatric-onset HPP, requires subcutaneous injections 3 to 6 times per week. We recently showed that a single injection of an adeno-associated virus vector serotype 8 harboring TNAP-D 10 (AAV8-TNAP-D 10 ) effectively prevented skeletal disease and prolonged life in Alpl -/- mice phenocopying infantile HPP. Here, we aimed to determine the efficacy of AAV8-TNAP-D 10 in improving the skeletal and dental phenotype in the Alpl Prx1/Prx1 and Phospho1 -/- mouse models of late-onset (adult) HPP and pseudo-HPP, respectively. A single dose of 3 × 10 11 vector genomes per body (vg/b) was injected intramuscularly into 8-week-old Alpl Prx1/Prx1 and wild-type (WT) littermates, or into 3-day-old Phospho1 -/- and WT mice, and treatment efficacy was evaluated after 60 days for late-onset HPP mice and after 90 days for Phospho1 -/- mice. Biochemical analysis showed sustained serum alkaline phosphatase activity and reduced plasma PP i levels, and radiographic images, micro-computed tomography (micro-CT) analysis, and hematoxylin and eosin (H&E) staining showed improvements in the long bones in the late-onset HPP mice and corrected scoliosis in the Phospho1 -/- mice. Micro-CT analysis of the dentoalveolar complex did not reveal significant changes in the phenotype of late-onset HPP and pseudo-HPP models. Moreover, alizarin red staining analysis showed that AAV8-TNAP-D 10 treatment did not promote ectopic calcification of soft organs in adult HPP mice after 60 days of treatment, even after inducing chronic kidney disease. Overall, the AAV8-TNAP-D 10 treatment improved the skeletal phenotype in both the adult HPP and pseudo-HPP mouse models. This preclinical study will contribute to the advancement of gene therapy for the improvement of skeletal disease in patients with heritable forms of osteomalacia. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: JLM is a consultant for Aruvant. JLM and KM are co‐inventors of a patent application for the use of viral‐mediated administration of mineral‐targeted TNAP for the treatment of HPP and pseudo‐HPP. FAO, FFM, YK, SN, CF, and BLF state that they have no conflicts of interest., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)