112 results on '"Osteomalacia pathology"'
Search Results
2. Approaching virtual osteoid volume estimation and in-depth tissue characterization in patients with tumor-induced osteomalacia.
- Author
-
Schmidt FN, Delsmann J, Yazigi B, Beil FT, Amling M, and Oheim R
- Subjects
- Humans, Female, Middle Aged, Male, Adult, Paraneoplastic Syndromes diagnostic imaging, Paraneoplastic Syndromes pathology, Aged, Ilium pathology, Ilium diagnostic imaging, Osteomalacia diagnostic imaging, Osteomalacia pathology
- Abstract
Tumor-induced osteomalacia (TIO) poses a significant diagnostic challenge, leading to increased disease duration and patient burden also by missing clinical suspicion. Today, diagnosis of osteomalacia relies on invasive iliac crest biopsy, if needed. Therefore, a noninvasive method would be beneficial for patients with severe osteomalacia, such as TIO, to inform their clinical management and address specific needs, like estimating the regeneration capacity at high osteoid volumes (OVs) or the potential of a hungry bone syndrome after tumor removal. Furthermore, given the lack of comprehensive histological characterization of TIO, there is a need for additional tissue characterization. Therefore, our assessment encompassed iliac crest biopsies that were examined using quantitative electron backscattered microscopy, Raman spectroscopy, micro-computed tomography, and histology to analyze the biopsy tissue. Our clinical assessment encompassed DXA and high-resolution peripheral quantitative computed tomography (HR-pQCT) alongside with biochemical analyses and clinical evaluations. Combining imaging and clinical data, we established a model to predict the OV. We compared 9 TIO patients with 10 osteoporosis (OPO) patients and 10 healthy controls. Histological analyses confirmed a pronounced OV in TIO patients (OPO: 1.20% ± 1.23% vs TIO: 23.55% ± 12.23%, P < .0005), and spectroscopy revealed lower phosphate levels in TIO biopsies. By combining HR-pQCT and laboratory diagnostics, we developed a linear regression model to noninvasively predict the OV revealing significantly higher modeled OV/BVmodel values of 24.46% ± 14.22% for TIO compared to the control group (5.952% ± 3.44%, P ≤ .001). By combining laboratory diagnostics, namely, ALP and Tt.BMDRadius measured by HR-pQCT, we achieved the calculation of the virtual osteoid volume to bone volume ratio (OV/BVmodel) with a significant correlation to histology as well as reliable identification of TIO patients compared to OPO and control. This novel approach is potentially helpful for predicting OV by noninvasive techniques in diagnostic procedures and improving the clinical management of TIO., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
- Published
- 2024
- Full Text
- View/download PDF
3. Tumor-induced Osteomalacia in a Boy with Maxillary Ossifying Fibroma
- Author
-
Thi HN, Manh CP, Tuan LT, Le Thi LA, Thanh NN, and Vilaiyuk S
- Subjects
- Male, Humans, Child, Adolescent, Osteomalacia etiology, Osteomalacia pathology, Fibroma, Ossifying complications, Fibroma, Ossifying diagnosis, Paraneoplastic Syndromes etiology, Paraneoplastic Syndromes pathology, Neoplasms
- Abstract
Tumor-induced osteomalacia (TIO) is a rare, paraneoplastic disorder of hypophosphatemia associated with elevated tumor-produced fibroblast growth factor 23 (FGF23). Maxillofacial tumors are rarely involved in TIO, especially maxillary TIO in children. We present a 14-year-old boy with osteomalacia and high serum levels of FGF23, a hormone associated with decreased phosphate resorption, due to a maxillary tumor. The patient was treated with oral phosphorus and calcitriol, and surgical removal of the tumor was performed. After 21 months follow-up, he was pain free and had returned to full activity. We review the reported pediatric cases of TIO in the maxillofacial and oral region and discuss the management of these patients considering the published evidence., Competing Interests: Conflict of interest: None declared, (©Copyright 2023 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)
- Published
- 2023
- Full Text
- View/download PDF
4. Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.
- Author
-
Fratzl-Zelman N, Linglart A, Bin K, Rauch F, Blouin S, Coutant R, and Donzeau A
- Subjects
- Child, Humans, Mutation, Alkaline Phosphatase genetics, Osteogenesis Imperfecta drug therapy, Osteogenesis Imperfecta genetics, Hypophosphatasia drug therapy, Hypophosphatasia genetics, Osteomalacia genetics, Osteomalacia pathology, Fractures, Multiple, Calcinosis, Rickets
- Abstract
Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence., Competing Interests: Declaration of competing interest NFZ, SB, FR, KB, RC, AD have no conflict of interest. AL: consulting fees from Alexion for the advisory board of the Hypophosphatasia registry, fees of investigator in the clinical trials received by my institution., (Copyright © 2023. Published by Elsevier Masson SAS.)
- Published
- 2023
- Full Text
- View/download PDF
5. [FGF23 tumor induced osteomalacia].
- Author
-
Gronskaia SA, Belaya ZE, and Melnichenko GA
- Subjects
- Humans, Fibroblast Growth Factors metabolism, Fibroblast Growth Factors therapeutic use, Vitamin D therapeutic use, Phosphorus therapeutic use, Osteomalacia etiology, Osteomalacia metabolism, Osteomalacia pathology, Neoplasms, Connective Tissue complications, Neoplasms, Connective Tissue diagnosis, Paraneoplastic Syndromes etiology, Paraneoplastic Syndromes diagnosis, Paraneoplastic Syndromes pathology
- Abstract
Tumor induced osteomalacia is a rare acquired disease. The cause is a mesenchymal tumor secreting fibroblast growth factor 23 (FGF23). An excessive amount of FGF 23 disrupts the metabolism of phosphorus and vitamin D, which leads to severe paraneoplastic syndrome, manifested in the form of multiple fractures, severe pain in the bones and generalized myopathy. With oncogenic osteomalacia, a complete cure is possible with radical resection of the tumor. Unfortunately, localization, small size of formations and rare frequency of occurrence lead to the fact that the disease remains unrecognized for a long time and leads to severe, disabling consequences. A step-by-step approach to diagnosis improves treatment outcomes. First, a thorough anamnesis is collected, then functional visualization is performed and the diagnosis is confirmed by anatomical visualization of the tumor. After that, the method of choice is a surgical treatment. If resection is not possible, then conservative therapy with active metabolites of vitamin D and phosphorus salts is indicated. New therapeutic approaches, such as the antibody to FGF23 or the pan-inhibitor of receptors to FGF, are actively developing. This article provides an overview of modern approaches to the diagnosis and treatment of this disease.
- Published
- 2022
- Full Text
- View/download PDF
6. Diagnostic Utility of Somatostatin Receptor 2A Immunohistochemistry for Tumor-induced Osteomalacia.
- Author
-
Lee S, Hong N, Shin S, Kim SI, Yun M, Kim SK, and Rhee Y
- Subjects
- Fibroblast Growth Factors metabolism, Humans, Immunohistochemistry, Retrospective Studies, Osteomalacia diagnosis, Osteomalacia etiology, Osteomalacia pathology, Paraneoplastic Syndromes diagnosis, Receptors, Somatostatin metabolism, Soft Tissue Neoplasms diagnosis
- Abstract
Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder caused by excessive fibroblast growth factor 23 (FGF23) secretion. FGF23 immunohistochemistry (IHC) is proposed as a useful adjunctive marker to confirm TIO diagnosis. However, it often stains focally, limiting its diagnostic utility., Objective: This work aimed to compare the diagnostic performance between somatostatin receptor 2A (SSTR2A) and FGF23 IHC for TIO., Methods: We retrospectively reviewed TIO-diagnosed patients in Severance Hospital between July 2006 and May 2020. Histologic evaluation was performed using histoscore (H score) (expression area proportion score [0-2] × intensity score [1-3], [total, 0-6]). FGF23 and SSTR2A IHC were performed using unstained slides from 18 localized TIO patients and 9 and 15 non-TIO controls with bone and soft-tissue tumors, respectively. SSTR2A positivity was defined as cytoplasmic, membranous, or Golgi staining in more than 1% of tumor cells, and negativity as nonspecific nuclear staining. FGF23 positivity was defined as cytoplasmic expression in more than 1% of the tumor area and negativity as nonspecific nuclear staining., Results: Suspicious lesions were successfully detected in 14 of 15 patients who underwent 68Ga-DOTATOC scans. Diffuse cytoplasmic SSTR2A expression was identified in all TIO patients and focal weak nuclear staining in 12 of 15 controls. FGF23 cytoplasmic expression was identified in 11 of 18 TIO patients and diffuse nuclear staining in 9 of 9 controls. The H score was higher in SSTR2A than in FGF23 IHC (median [interquartile range]: 6 [6-6] vs 1 [0-2], P < .001)., Conclusion: SSTR2A IHC with H-score quantification might be a more sensitive, adjunctive diagnostic tool than FGF23 IHC for TIO diagnosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
7. Bone Impairment in a Large Cohort of Chinese Patients With Tumor-Induced Osteomalacia Assessed by HR-pQCT and TBS.
- Author
-
Ni X, Feng Y, Guan W, Chi Y, Li X, Gong Y, Zhao N, Pang Q, Yu W, Wu H, Huo L, Liu Y, Jin J, Zhou X, Lv W, Zhou L, Xia Y, Liu W, Jiajue R, Wang O, Li M, Xing X, Fukumoto S, Jiang Y, and Xia W
- Subjects
- Absorptiometry, Photon methods, Bone Density, China, Humans, Lumbar Vertebrae, Radius pathology, Tibia pathology, Bone Diseases, Metabolic pathology, Osteomalacia diagnostic imaging, Osteomalacia pathology, Paraneoplastic Syndromes diagnostic imaging
- Abstract
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density (aBMD) in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral (distal radius and tibia) and axial (lumbar spine) skeleton using high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry (DXA) or HR-pQCT scans were enrolled. Compared with age-, sex-, and body mass index (BMI)-matched healthy controls, TIO patients (n = 113) had lower volumetric BMD, damaged microstructure, and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS (<1.35) was higher than that with low L
1 to L4 aBMD Z-score (Z ≤ -2) (43.9% versus 89.6%, p < 0.001). Higher intact fibroblast growth factor 23 (iFGF23), intact parathyroid hormone (iPTH), alkaline phosphatase, and β-isomerized C-terminal telopeptide of type I collagen (β-CTx) levels, more severe mobility impairment, and a history of fracture were associated with poorer HR-pQCT parameters but not with lower TBS. However, greater height loss and longer disease duration were correlated with worse HR-pQCT parameters and TBS. Moreover, TBS was correlated with both trabecular and cortical HR-pQCT parameters in TIO. In conclusion, we revealed impaired bone microarchitecture in the axial and peripheral skeleton in a large cohort of Chinese TIO patients. HR-pQCT parameters and TBS showed promising advantages over aBMD for assessing bone impairment in patients with TIO. A longer follow-up period is needed to observe changes in bone microarchitecture after tumor resection. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)- Published
- 2022
- Full Text
- View/download PDF
8. Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors.
- Author
-
Zavatta G, Altieri P, Vandi G, Vicennati V, Pagotto U, and Vescini F
- Subjects
- Bone and Bones metabolism, Calcium blood, Humans, Hyperparathyroidism, Primary pathology, Hypoparathyroidism pathology, Hypophosphatemia pathology, Phosphates metabolism, Multiple Endocrine Neoplasia pathology, Osteomalacia pathology, Parathyroid Diseases pathology, Parathyroid Glands metabolism, Phosphates blood
- Abstract
The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.
- Published
- 2021
- Full Text
- View/download PDF
9. Prolonged Hypophosphatemia and Intensive Care After Curative Surgery of Tumor Induced Osteomalacia: A Case Report.
- Author
-
Ryhänen EM, Schalin-Jäntti C, and Matikainen N
- Subjects
- Female, Fibroblast Growth Factors blood, Humans, Hypophosphatemia blood, Hypophosphatemia pathology, Mandibular Neoplasms blood, Mandibular Neoplasms complications, Mandibular Neoplasms pathology, Middle Aged, Osteomalacia blood, Osteomalacia pathology, Paraneoplastic Syndromes blood, Hypophosphatemia etiology, Mandibular Neoplasms surgery, Osteomalacia surgery, Paraneoplastic Syndromes surgery, Phosphates blood
- Abstract
Introduction: Rare FGF23-producing mesenchymal tumors lead to paraneoplastic tumor-induced osteomalacia (TIO) presenting with phosphate wasting, hypophosphatemia, chronic hypomineralization of the bone, fragility fractures and muscle weakness. Diagnosis of TIO requires exclusion of other etiologies and careful search for a mesenchymal tumor that often is very small and can appear anywhere in the body. Surgical removal of the tumor is the only definitive treatment of TIO. Surgical complications due to chronic hypophosphatemia are not well recognized., Case Description: The current case describes severe fragility fractures in a 58-year-old woman, who lost her ability to walk and was bedridden for two years. First, the initial diagnostic laboratory work-up did not include serum phosphorus measurements, second, the suspicion of adverse effects of pioglitazone as an underlying cause delayed correct diagnosis for at least two years. After biochemical discovery of hyperphosphaturic hypophosphatemia at a tertiary referral centre, a FGF23-producing tumor of the mandible was discovered on physical examination, and then surgically removed. Postoperatively, severe hypophosphatemia and muscle weakness prolonged the need for ventilation support, intensive care and phosphate supplementation. After two years of rehabilitation, the patient was able to walk short distances. The tumor has not recurred, and serum phosphate concentration has remained within normal limits during 3.5 years of follow-up., Conclusions: The case report illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Compared to other low phosphate conditions, surgical recovery from TIO-induced hypophosphatemia warrants special attention. Increased alkaline phosphatase concentration may indicate impaired postsurgical recovery due to prolonged hypophosphatemia, underlining the need for proactive perioperative correction of hypophosphatemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ryhänen, Schalin-Jäntti and Matikainen.)
- Published
- 2021
- Full Text
- View/download PDF
10. Liquid-phase ASEM imaging of cellular and structural details in cartilage and bone formed during endochondral ossification: Keap1-deficient osteomalacia.
- Author
-
Sakai E, Sato M, Memtily N, Tsukuba T, and Sato C
- Subjects
- Animals, Bone and Bones diagnostic imaging, Calcification, Physiologic, Cartilage diagnostic imaging, Cartilage pathology, Chondrogenesis, Cortical Bone diagnostic imaging, Cortical Bone ultrastructure, Embryo, Mammalian diagnostic imaging, Femur diagnostic imaging, Femur ultrastructure, Imaging, Three-Dimensional, Kelch-Like ECH-Associated Protein 1 metabolism, Mice, Inbred C57BL, Osteocytes metabolism, Phenotype, Tibia diagnostic imaging, Tibia ultrastructure, Mice, Atmosphere, Bone and Bones pathology, Bone and Bones ultrastructure, Cartilage ultrastructure, Kelch-Like ECH-Associated Protein 1 deficiency, Microscopy, Electron, Scanning, Osteogenesis, Osteomalacia pathology
- Abstract
Chondrogenesis and angiogenesis drive endochondral ossification. Using the atmospheric scanning electron microscopy (ASEM) without decalcification and dehydration, we directly imaged angiogenesis-driven ossification at different developmental stages shortly after aldehyde fixation, using aqueous radical scavenger glucose solution to preserve water-rich structures. An embryonic day 15.5 mouse femur was fixed and stained with phosphotungstic acid (PTA), and blood vessel penetration into the hypertrophic chondrocyte zone was visualised. We observed a novel envelope between the perichondrium and proliferating chondrocytes, which was lined with spindle-shaped cells that could be borderline chondrocytes. At postnatal day (P)1, trabecular and cortical bone mineralisation was imaged without staining. Additional PTA staining visualised surrounding soft tissues; filamentous connections between osteoblast-like cells and osteocytes in cortical bone were interpreted as the osteocytic lacunar-canalicular system. By P10, resorption pits had formed on the tibial trabecular bone surface. The applicability of ASEM for pathological analysis was addressed using knockout mice of Keap1, an oxidative-stress sensor. In Keap1
-/- femurs, we observed impaired calcification and angiogenesis of epiphyseal cartilage, suggesting impaired bone development. Overall, the quick ASEM method we developed revealed mineralisation and new structures in wet bone tissue at EM resolution and can be used to study mineralisation-associated phenomena of any hydrated tissue.- Published
- 2021
- Full Text
- View/download PDF
11. Medication-Related Osteonecrosis of the Jaw (MRONJ): Are Antiresorptive Drugs the Main Culprits or Only Accomplices? The Triggering Role of Vitamin D Deficiency.
- Author
-
Dalle Carbonare L, Mottes M, and Valenti MT
- Subjects
- Animals, Humans, Mandible pathology, Maxilla pathology, Osteomalacia pathology, Vitamin D Deficiency pathology, Bisphosphonate-Associated Osteonecrosis of the Jaw etiology, Bone Density Conservation Agents adverse effects, Diphosphonates adverse effects, Osteomalacia complications, Vitamin D Deficiency complications
- Abstract
Osteonecrosis of the jaw (ONJ) is a severe clinical condition characterized mostly but not exclusively by an area of exposed bone in the mandible and/or maxilla that typically does not heal over a period of 6-8 weeks. The diagnosis is first of all clinical, but an imaging feedback such as Magnetic Resonance is essential to confirm clinical suspicions. In the last few decades, medication-related osteonecrosis of the jaw (MRONJ) has been widely discussed. From the first case reported in 2003, many case series and reviews have appeared in the scientific literature. Almost all papers concerning this topic conclude that bisphosphonates (BPs) can induce this severe clinical condition, particularly in cancer patients. Nevertheless, the exact mechanism by which amino-BPs would be responsible for ONJ is still debatable. Recent findings suggest a possible alternative explanation for BPs role in this pattern. In the present work we discuss how a condition of osteomalacia and low vitamin D levels might be determinant factors.
- Published
- 2021
- Full Text
- View/download PDF
12. Hypophosphatemic Hypovitaminosis D Induces Osteomalacia in the Adult Female Rat.
- Author
-
Durup D, Diaz-delCastillo M, Morgenlykke J, Jensen LT, Frandsen E, Abelson KSP, Pedersen L, Lykkesfeldt J, Ding M, Jørgensen NR, Syberg S, Petersen S, and Heegaard AM
- Subjects
- Animals, Bone Remodeling, Bone and Bones metabolism, Calcification, Physiologic, Calcium blood, Calcium urine, Female, Hypophosphatemia metabolism, Hypophosphatemia pathology, Osteomalacia metabolism, Osteomalacia pathology, Phosphates blood, Phosphates urine, Phosphorus blood, Phosphorus urine, Rats, Rats, Sprague-Dawley, Vitamin D analogs & derivatives, Vitamin D blood, Vitamin D Deficiency metabolism, Vitamin D Deficiency pathology, Hypophosphatemia complications, Osteomalacia etiology, Vitamin D Deficiency complications
- Abstract
Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D-depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D-depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
13. Osteoidosis leads to altered differentiation and function of osteoclasts.
- Author
-
Grünherz L, Prein C, Winkler T, Kirsch M, Hopfner U, Streichert T, Clausen-Schaumann H, Zustin J, Kirchhof K, Morlock MM, Machens HG, and Schilling AF
- Subjects
- Biopsy, Bone and Bones metabolism, Bone and Bones pathology, Calcification, Physiologic, Cell Count, Cells, Cultured, Extracellular Matrix metabolism, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, Microscopy, Atomic Force, Osteoblasts metabolism, Osteomalacia pathology, Retrospective Studies, Transcriptome, Cell Differentiation genetics, Osteoclasts cytology, Osteoclasts metabolism, Osteomalacia etiology, Osteomalacia metabolism
- Abstract
In patients with osteomalacia, a defect in bone mineralization leads to changed characteristics of the bone surface. Considering that the properties of the surrounding matrix influence function and differentiation of cells, we aimed to investigate the effect of osteoidosis on differentiation and function of osteoclasts. Based on osteomalacic bone biopsies, a model for osteoidosis in vitro (OIV) was established. Peripheral blood mononuclear cells were differentiated to osteoclasts on mineralized surfaces (MS) as internal control and on OIV. We observed a significantly reduced number of osteoclasts and surface resorption on OIV. Atomic force microscopy revealed a significant effect of the altered degree of mineralization on surface mechanics and an unmasking of collagen fibres on the surface. Indeed, coating of MS with RGD peptides mimicked the resorption phenotype observed in OIV, suggesting that the altered differentiation of osteoclasts on OIV might be associated with an interaction of the cells with amino acid sequences of unmasked extracellular matrix proteins containing RGD sequences. Transcriptome analysis uncovered a strong significant up-regulation of transmembrane glycoprotein TROP2 in osteoclastic cultures on OIV. TROP2 expression on OIV was also confirmed on the protein level and found on the bone surface of patients with osteomalacia. Taken together, our results show a direct influence of the mineralization state of the extracellular matrix surface on differentiation and function of osteoclasts on this surface which may be important for the pathophysiology of osteomalacia and other bone disorders with changed ratio of osteoid to bone., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
14. Tumour-induced osteomalacia due to an intra-abdominal mesenchymal tumour.
- Author
-
Krishnappa B, Jadhav SR, Lila AR, and Bandgar TR
- Subjects
- Abdominal Neoplasms diagnosis, Abdominal Neoplasms diagnostic imaging, Abdominal Neoplasms pathology, Fibroblast Growth Factor-23, Humans, Male, Middle Aged, Osteomalacia diagnostic imaging, Osteomalacia pathology, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms diagnostic imaging, Soft Tissue Neoplasms pathology, Abdominal Neoplasms complications, Osteomalacia etiology, Soft Tissue Neoplasms complications
- Abstract
A 50-year-man presented with debilitating lower-limb proximal muscle weakness and hip pain since 3 years. Investigations (serum calcium (8.9 mg/dL), serum phosphorus (1.5 mg/dL), serum albumin (40 g/L), parathyroid hormone (116 pg/mL (12.30 pmol/L)), 25(OH)D3 (25.2 ng/mL (63 nmol/L)) 1,25(OH)
2 D3 (19 pg/mL (45.60 pmol/L)), tubular reabsorption of phosphate of 0.22 and elevated serum fibroblast growth factor 23 (FGF23) (387.7 RU/mL)) were consistent with tumour-induced osteomalacia (TIO). Localisation studies (68 Ga DOTATATE positron emission tomography (PET)/CT and18 FDG-PET/CT) did not reveal any lesion. Re-evaluation after 2 and 5 years with68 Ga-DOTANOC PET/CT showed 2×1.4 cm progressively increasing rounded soft tissue enhancing mass close to splenic hilum (SUV max: 26.4). Tumour was resected by laparotomy. Both FGF23 (120 RU/mL on day 3) and serum phosphorus (2.5 mg/dL on day 10) normalised with significant clinical improvement after surgery. Histopathology revealed phosphaturic mesenchymal tumour. Here, we report the first case of intra-abdominal mesenchymal tumour causing TIO diagnosed by serial functional imaging., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2019
- Full Text
- View/download PDF
15. Severe Osteomalacia with Dent Disease Caused by a Novel Intronic Mutation of the CLCN5 gene.
- Author
-
Matsumoto A, Matsui I, Mori T, Sakaguchi Y, Mizui M, Ueda Y, Takahashi A, Doi Y, Shimada K, Yamaguchi S, Kubota K, Hashimoto N, Oka T, Takabatake Y, Sohara E, Hamano T, Uchida S, and Isaka Y
- Subjects
- Adult, Calcium, Dietary therapeutic use, Dent Disease complications, Dent Disease pathology, Dietary Supplements, Humans, Introns, Japan, Kidney Tubules, Proximal pathology, Male, Medication Adherence, Osteomalacia drug therapy, Osteomalacia etiology, Osteomalacia pathology, Vitamin D therapeutic use, Vitamins therapeutic use, Chloride Channels genetics, Dent Disease genetics, Osteomalacia genetics, Point Mutation
- Abstract
We present a case of Dent disease caused by a novel intronic mutation, 1348-1G>A, of the chloride voltage-gated channel 5 (CLCN5) gene. Cultured proximal tubule cells obtained from the patient showed impaired acidification of the endosome and/or lysosome, indicating that the 1348-1G>A mutation was indeed the cause of Dent disease. Although the prevalence of osteomalacia in Dent disease is low in Japan, several factors-including poor medication adherence-caused severe osteomalacia in the current case. Oral supplementation with calcium and native/active vitamin D therapy, with careful attention to medication adherence, led to the improvement of the patient's bone status.
- Published
- 2018
- Full Text
- View/download PDF
16. Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype.
- Author
-
Kamiya N, Yamaguchi R, Aruwajoye O, Kim AJ, Kuroyanagi G, Phipps M, Adapala NS, Feng JQ, and Kim HK
- Subjects
- Animals, Fibroblast Growth Factor-23, Fibroblast Growth Factors genetics, Humans, Mice, Mice, Knockout, Neurofibromatosis 1 genetics, Neurofibromatosis 1 metabolism, Neurofibromatosis 1 pathology, Bone Neoplasms genetics, Bone Neoplasms metabolism, Bone Neoplasms pathology, Fibroblast Growth Factors metabolism, Neurofibromin 1 deficiency, Osteocytes metabolism, Osteocytes pathology, Osteoma, Osteoid genetics, Osteoma, Osteoid metabolism, Osteoma, Osteoid pathology, Osteomalacia genetics, Osteomalacia metabolism, Osteomalacia pathology
- Abstract
Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia-like bone phenotype. Serum FGF23 levels were 4 times increased in cKO mice compared with age-matched controls. In addition, calcium-phosphorus metabolism was significantly altered (calcium reduced; phosphorus reduced; parathyroid hormone [PTH] increased; 1,25(OH)
2 D decreased). Bone histomorphometry showed dramatically increased osteoid parameters, including osteoid volume, surface, and thickness. Dynamic bone histomorphometry revealed reduced bone formation rate and mineral apposition rate in the cKO mice. TRAP staining showed a reduced osteoclast number. Micro-CT demonstrated thinner and porous cortical bones in the cKO mice, in which osteocyte dendrites were disorganized as assessed by electron microscopy. Interestingly, the cKO mice exhibited spontaneous fractures in long bones, as found in NF1 patients. Mechanical testing of femora revealed significantly reduced maximum force and stiffness. Immunohistochemistry showed significantly increased FGF23 protein in the cKO bones. Moreover, primary osteocytes from cKO femora showed about eightfold increase in FGF23 mRNA levels compared with control cells. The upregulation of FGF23 was specifically and significantly inhibited by PI3K inhibitor Ly294002, indicating upregulation of FGF23 through PI3K in Nf1-deficient osteocytes. Taken together, these results indicate that Nf1 deficiency in osteocytes dramatically increases FGF23 production and causes a mineralization defect (ie, hyperosteoidosis) via the alteration of calcium-phosphorus metabolism. This study demonstrates critical roles of neurofibromin in osteocytes for osteoid mineralization. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)- Published
- 2017
- Full Text
- View/download PDF
17. A distinctive patchy osteomalacia characterises Phospho1-deficient mice.
- Author
-
Boyde A, Staines KA, Javaheri B, Millan JL, Pitsillides AA, and Farquharson C
- Subjects
- Animals, Calcification, Physiologic physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Bone and Bones pathology, Bone and Bones ultrastructure, Osteomalacia pathology, Phosphoric Monoester Hydrolases deficiency
- Abstract
The phosphatase PHOSPHO1 is involved in the initiation of biomineralisation. Bones in Phospho1 knockout (KO) mice show histological osteomalacia with frequent bowing of long bones and spontaneous fractures: they contain less mineral, with smaller mineral crystals. However, the consequences of Phospho1 ablation on the microscale structure of bone are not yet fully elucidated. Tibias and femurs obtained from wild-type and Phospho1 null (KO) mice (25-32 weeks old) were embedded in PMMA, cut and polished to produce near longitudinal sections. Block surfaces were studied using 20 kV backscattered-electron (BSE) imaging, and again after iodine staining to reveal non-mineralised matrix and cellular components. For 3D characterisation, we used X-ray micro-tomography. Bones opened with carbide milling tools to expose endosteal surfaces were macerated using an alkaline bacterial pronase enzyme detergent, 5% hydrogen peroxide and 7% sodium hypochlorite solutions to produce 3D surfaces for study with 3D BSE scanning electron microscopy (SEM). Extensive regions of both compact cortical and trabecular bone matrix in Phospho1 KO mice contained no significant mineral and/or showed arrested mineralisation fronts, characterised by a failure in the fusion of the calcospherite-like, separately mineralising, individual micro-volumes within bone. Osteoclastic resorption of the uncalcified matrix in Phospho1 KO mice was attenuated compared with surrounding normally mineralised bone. The extent and position of this aberrant biomineralisation varied considerably between animals, contralateral limbs and anatomical sites. The most frequent manifestation lay, however, in the nearly complete failure of mineralisation in the bone surrounding the numerous transverse blood vessel canals in the cortices. In conclusion, SEM disclosed defective mineralising fronts and extensive patchy osteomalacia, which has previously not been recognised. These data further confirm the role of this phosphatase in physiological skeletal mineralisation., (© 2017 Anatomical Society.)
- Published
- 2017
- Full Text
- View/download PDF
18. Fibrogenesis Imperfecta Ossium and Response to Human Growth Hormone: A Potential Therapy.
- Author
-
Bhadada SK, Dhiman V, Mukherjee S, Aggarwal S, Bal A, Sukumar SP, Sood A, Sharma DC, Khandelwal N, Bhansali A, Van Hul W, and Rao SD
- Subjects
- Adult, Alkaline Phosphatase metabolism, Bone Diseases, Metabolic complications, Bone Diseases, Metabolic metabolism, Bone Diseases, Metabolic pathology, Bone and Bones metabolism, Bone and Bones pathology, Bone and Bones ultrastructure, Calcification, Physiologic, Fractures, Bone etiology, Fractures, Spontaneous etiology, Humans, Male, Microscopy, Electron, Transmission, Middle Aged, Musculoskeletal Pain etiology, Osteomalacia etiology, Osteomalacia metabolism, Osteomalacia pathology, Siblings, Treatment Outcome, Bone Diseases, Metabolic drug therapy, Human Growth Hormone therapeutic use, Recombinant Proteins therapeutic use
- Abstract
Context: Fibrogenesis imperfecta ossium (FIO) is a rare bone disease manifested by generalized bone pain, fragility fractures, progressive disability, and extensive mineralization defect seen in bone biopsy specimens. The pathogenesis of the disease is unknown and currently there is no effective treatment., Objective: To report on the effect of recombinant human growth hormone (rhGH) therapy in FIO., Design: An observational study in two patients., Setting: Endocrinology clinic in an academic institution., Patients or Other Participants: Two siblings with FIO., Intervention(s): rhGH was administered subcutaneously at a dose of 1 U daily for 1 year., Main Outcome Measures: Changes in clinical, biochemical, radiological, and bone histological (i.e., light and transmission electron microscopy, and histomorphometry) investigations., Results: Except for an elevated serum alkaline phosphatase level, results of routine biochemical, hematological, and hormonal investigations were normal in both patients. Radiographs showed pseudofractures and bone scans revealed a "beheaded" tracer activity pattern (i.e., superscan without uptake in the skull). Bone biopsy specimens showed severe mineralization defect simulating osteomalacia with disorganized collagen fibril alignment. Treatment with rhGH was followed by clinical, biochemical, and radiological improvement in both the patients, with substantial improvement in the mineralization defect, most likely due to rhGH-induced improvement in collagen fibril arrangement., Conclusion: We report on two brothers with FIO and demonstrate clinical improvement and restoration of normal bone pathology with rhGH therapy. We suggest that rhGH is a potential therapy for FIO for which no effective therapy currently exists., (Copyright © 2017 Endocrine Society)
- Published
- 2017
- Full Text
- View/download PDF
19. Bone Histology of Two Cases with Osteomalacia Related to Low-dose Adefovir.
- Author
-
Hiramatsu R, Ubara Y, Sawa N, Hasegawa E, Kawada M, Imafuku A, Sumida K, Hoshino J, and Takaichi K
- Subjects
- Adenine adverse effects, Aged, Bone Density Conservation Agents therapeutic use, Fanconi Syndrome complications, Female, Hepatitis B, Chronic drug therapy, Humans, Hypophosphatemia complications, Musculoskeletal Pain etiology, Musculoskeletal Pain pathology, Musculoskeletal Pain therapy, Risedronic Acid therapeutic use, Adenine analogs & derivatives, Antiviral Agents adverse effects, Organophosphonates adverse effects, Osteomalacia chemically induced, Osteomalacia pathology
- Abstract
We performed a bone histomorphometric analysis in two patients demonstrating Fanconi syndrome with hypophosphatemia, adefovir-related bone disease and chronic hepatitis B infection. Both patients had osteomalacia, but showed two different histological patterns. The osteoid volume of the patient without risedronate increased with [(osteoid volume/ bone volume)×100=18.6%]. However, the osteoid volume of the patient receiving risedronate without vitamin D analogue showed a greater increase of 53.8%. In both patients bone pain and hypophosphatemia subsided soon after the discontinuation of adefovir and the administration of phosphate derivative. These findings show that bisphosphonate may worsen this disease when this drug is administered without a vitamin D analogue.
- Published
- 2016
- Full Text
- View/download PDF
20. En bloc resection for treatment of tumor-induced osteomalacia: a case presentation and a systematic review.
- Author
-
Meng T, Zhou W, Li B, Yin H, Li Z, Zhou L, Kong J, Yan W, Yang X, Liu T, Song D, and Xiao J
- Subjects
- Humans, Hypophosphatemia diagnosis, Indium Radioisotopes, Magnetic Resonance Imaging, Male, Mesenchymoma diagnostic imaging, Mesenchymoma pathology, Middle Aged, Octreotide, Osteomalacia diagnostic imaging, Osteomalacia pathology, Positron-Emission Tomography, Spinal Neoplasms diagnostic imaging, Spinal Neoplasms pathology, Mesenchymoma surgery, Osteomalacia surgery, Spinal Neoplasms surgery
- Abstract
Background: Tumor-induced osteomalacia (TIO) is a rare disorder, which is commonly found in craniofacial locations and in the extremities. To the best of our knowledge, only 16 cases have been described in the spine, and this is the first report to describe a case of patient with TIO in the thoracic spine combined with a mesenchymal hamartoma which had confused the therapeutic strategies to date., Case Description: We report the case of a 60-year-old patient with hypophosphatemia and presented with limb weakness. Treating with phosphate did not correct the hypophosphatemia and an (111)In pentetreotide scintigraphy (octreotide scan) revealed an increased uptake at the right forearm. The tumor was resected totally, and the histopathology revealed a mesenchymal hamartoma, but we noticed that hypophosphatemia was not corrected after the tumor resection. Then a whole-body magnetic resonance imaging (WB-MRI) was performed and the results revealed tumorous tissues at the right T1 vertebral pedicle. The tumor was removed with an en bloc method, and the pathology showed phosphaturic mesenchymal tumor. Follow-up at 1 year after surgery revealed no recurrence, and the serum phosphorus level of the patient was normal., Conclusions: Tumor-induced osteomalacia is exceedingly rare with only 16 cases in spine published in the literature. It is difficult to find and leads to years of suffering debilitating complications. In this regard, the WB-MRI is a better method to locate the real tumor. Treating with phosphate can only relieve symptoms, and a complete surgical removal remains the gold standard treatment.
- Published
- 2015
- Full Text
- View/download PDF
21. [Bone and Joint Involvement in Celiac Disease].
- Author
-
Hoffmanová I, Sánchez D, and Džupa V
- Subjects
- Celiac Disease diagnosis, Diet, Gluten-Free adverse effects, Female, Humans, Male, Osteomalacia pathology, Osteoporosis pathology, Recurrence, Bone and Bones pathology, Celiac Disease pathology, Fractures, Bone pathology
- Abstract
Celiac disease (gluten-sensitive enteropathy) is currently regarded as a multisystem autoimmune disorder; its clinical signs and symptoms do not involve merely the gastrointestinal tract but are associated with several other medical specialties, including orthopaedics and traumatology. In orthopaedic and trauma patients, celiac disease should be suspected in the following diagnoses: osteomalacia, premenopausal osteoporosis, post-menopausal osteoporosis more severe than expected and refractory to medication, osteoporosis in men under 55 years of age, recurrent bone fractures in the limbs, large joint arthralgia or arthritis of unclear aetiology, erosive spondyloarthropathy particularly in patients with the history of chronic diarrhoea, anaemia or associated autoimmune disorders (type 1 diabetes mellitus or autoimmune thyreopathy), and in women with secondary amenorrhea or early menopause. The orthopaedist or trauma surgeon should be aware of suspected celiac disease in patients who do not respond adequately to the standard treatment of pain related to the musculoskeletal system, in patients with recurrent fractures of the limb bones and in young patients with suspected secondary osteoporosis. With the use of appropriate screening methods, celiac disease as-yet undiagnosed can be revealed. A long-life gluten-free diet in these patients results in the alleviation of metabolic osteopathy and joint and muscle problems, in reduced requirements of analgesic and antiphlogistic drugs as well as in reduced risks of fracture.
- Published
- 2015
22. Tumour-induced osteomalacia.
- Author
-
Bhatt AA, Mathews SS, Kumari A, and Paul TV
- Subjects
- Adult, Female, Humans, Hypophosphatemia pathology, Osteomalacia diagnosis, Osteomalacia pathology, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms pathology, Hypophosphatemia etiology, Osteomalacia etiology, Soft Tissue Neoplasms complications
- Published
- 2014
- Full Text
- View/download PDF
23. A 40-year-old woman with intracranial bleed and osteomalacia.
- Author
-
Gulwani H and Garg N
- Subjects
- Adult, Brain surgery, Brain Neoplasms physiopathology, Cerebral Angiography, Female, Hemangiopericytoma physiopathology, Humans, Intracranial Hemorrhages physiopathology, Lipoma physiopathology, Magnetic Resonance Imaging, Osteomalacia physiopathology, Rectal Neoplasms physiopathology, Brain pathology, Brain Neoplasms pathology, Hemangiopericytoma pathology, Intracranial Hemorrhages pathology, Lipoma pathology, Osteomalacia pathology, Rectal Neoplasms pathology
- Published
- 2014
- Full Text
- View/download PDF
24. Histopathological analysis for osteomalacia and tubulopathy in itai-itai disease.
- Author
-
Baba H, Tsuneyama K, Kumada T, Aoshima K, and Imura J
- Subjects
- Aged, Aged, 80 and over, Bone and Bones pathology, Cadmium Poisoning etiology, Female, Humans, Kidney pathology, Kidney Diseases metabolism, Kidney Tubules metabolism, Kidney Tubules pathology, Male, Middle Aged, Osteomalacia metabolism, Bone and Bones metabolism, Cadmium Compounds analysis, Cadmium Compounds toxicity, Cadmium Poisoning metabolism, Cadmium Poisoning pathology, Environmental Pollutants analysis, Kidney metabolism, Kidney Diseases etiology, Kidney Diseases pathology, Osteomalacia etiology, Osteomalacia pathology
- Abstract
Background & Aims: Cadmium (Cd) is a widespread environmental contaminant that causes both renal tubulopathy and osteomalacia. Osteomalacia is thought to be a result of renal tubulopathy, but there are few studies about the histopathological relationship between the two pathoses. Therefore, in the present study, we examined specimens from cases of itai-itai disease (IID), the most severe form of chronic cadmium poisoning, to evaluate the relationship between them., Methods: We analyzed kidney and bone specimens of 61 IID cases and the data regarding Cd concentration in kidney and bone. Tubulopathy was graded on the basis of a three-step scale (mild, moderate, and severe) using the following three items: the degree of proximal tubular defluxion, thickness of renal cortex, and weight of the kidney. Osteomalacia was evaluated using the relative osteoid volume (ROV)., Results: There were 15 cases of mild, 19 cases of moderate, and 27 cases of severe tubulopathy. The average ROV was 24.9 ± 2.0%. ROV tended to increase as tubulopathy advanced in severity, and ROV was significantly higher in cases with severe tubulopathy than those with mild or moderate tubulopathy. ROV had a negative correlation with Cd concentration in the kidney but no correlation with that in the bone., Conclusions: Our results suggest that the development of osteomalacia was related to the development of tubulopathy.
- Published
- 2014
- Full Text
- View/download PDF
25. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.
- Author
-
Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, Kelley PK, Jüppner H, Gottschalk M, Tifft CJ, Gafni RI, Boyce AM, Cowen EW, Bhattacharyya N, Guthrie LC, Gahl WA, Golas G, Loring EC, Overton JD, Mane SM, Lifton RP, Levy ML, Collins MT, and Choate KA
- Subjects
- Adolescent, Child, Exome, Female, Fibroblast Growth Factor-23, Fibroblast Growth Factors genetics, Gene Expression Regulation, Developmental, Humans, Hypophosphatemia blood, Hypophosphatemia pathology, Male, Mutation, Nevus, Nevus, Pigmented blood, Nevus, Pigmented pathology, Osteomalacia blood, Osteomalacia pathology, Sequence Analysis, DNA, Skin metabolism, Skin pathology, Skin Neoplasms blood, Skin Neoplasms pathology, Fibroblast Growth Factors blood, GTP Phosphohydrolases genetics, Hypophosphatemia genetics, Membrane Proteins genetics, Nevus, Pigmented genetics, Osteomalacia genetics, Proto-Oncogene Proteins p21(ras) genetics, Skin Neoplasms genetics
- Abstract
Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
- Published
- 2014
- Full Text
- View/download PDF
26. Genomic study of ossification of the posterior longitudinal ligament of the spine.
- Author
-
Ikegawa S
- Subjects
- Animals, Humans, Hypoparathyroidism complications, Hypoparathyroidism genetics, Hypoparathyroidism pathology, Japan, Ossification of Posterior Longitudinal Ligament pathology, Osteomalacia complications, Osteomalacia genetics, Osteomalacia pathology, Spinal Cord pathology, Genome-Wide Association Study, Multifactorial Inheritance, Ossification of Posterior Longitudinal Ligament genetics
- Abstract
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common disease after the middle age. OPLL frequently causes serious neurological problems due to compression of the spinal cord and/or nerve roots. OPLL occurs in patients with monogenic metabolic diseases including rickets/osteomalacia and hypoparathyroidism; however most of OPLL is idiopathic and is considered as a multi-factorial (polygenic) disease influenced by genetic and environmental factors. Genomic studies for the genetic factors of OPLL have been conducted, mainly in Japan, including linkage and association studies. This paper reviews the recent progress in the genomic study of OPLL and comments on its future direction.
- Published
- 2014
- Full Text
- View/download PDF
27. Debilitating bone pain in a patient with celiac disease.
- Author
-
Werling S, Müller M, and Eckardt AJ
- Subjects
- Aged, Double-Balloon Enteroscopy, Hip diagnostic imaging, Humans, Lumbosacral Region diagnostic imaging, Male, Tomography, X-Ray Computed, Celiac Disease complications, Musculoskeletal Pain etiology, Osteomalacia diagnosis, Osteomalacia pathology
- Published
- 2013
- Full Text
- View/download PDF
28. Whole-body MR imaging in detecting phosphaturic mesenchymal tumor (PMT) in tumor-induced hypophosphatemic osteomalacia.
- Author
-
Nakanishi K, Sakai M, Tanaka H, Tsuboi H, Hashimoto J, Hashimoto N, and Tomiyama N
- Subjects
- Adult, Diagnosis, Differential, Female, Humans, Middle Aged, Whole Body Imaging methods, Hypophosphatemia etiology, Hypophosphatemia pathology, Magnetic Resonance Imaging methods, Mesenchymoma complications, Mesenchymoma pathology, Osteomalacia etiology, Osteomalacia pathology
- Abstract
We present 2 cases of tumor-induced osteomalacia (TIO). Both patients had histories of long-term bone and muscle pain. Laboratory data revealed hypophosphatemia. Whole-body magnetic resonance (MR) imaging (WB-MRI) clearly depicted a small subcutaneous mass in the left thigh of the first patient and a right acetabular mass in the second patient. These lesions were pathologically proven to be hemangiopericytoma-phosphaturic mesenchymal tumors (PMT).
- Published
- 2013
- Full Text
- View/download PDF
29. Amelogenesis imperfecta and other biomineralization defects in Fam20a and Fam20c null mice.
- Author
-
Vogel P, Hansen GM, Read RW, Vance RB, Thiel M, Liu J, Wronski TJ, Smith DD, Jeter-Jones S, and Brommage R
- Subjects
- Alkaline Phosphatase blood, Amelogenesis Imperfecta metabolism, Amelogenesis Imperfecta pathology, Animals, Calcium blood, Calcium-Binding Proteins metabolism, Dental Enamel Proteins genetics, Dental Enamel Proteins metabolism, Disease Models, Animal, Extracellular Matrix Proteins metabolism, Female, Fibroblast Growth Factor-23, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteomalacia metabolism, Osteomalacia pathology, Phenotype, Phosphorus blood, Proteins metabolism, Radiography, Rickets metabolism, Rickets pathology, Tooth diagnostic imaging, Tooth metabolism, Tooth pathology, Tooth Calcification, Amelogenesis Imperfecta veterinary, Calcium-Binding Proteins genetics, Extracellular Matrix Proteins genetics, Osteomalacia veterinary, Proteins genetics, Rickets veterinary
- Abstract
The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b (-/-) embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a (-/-) mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c (-/-) mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c (-/-) mice.
- Published
- 2012
- Full Text
- View/download PDF
30. Striking pathology gold: a singular experience with daily reverberations: sinonasal hemangiopericytoma (glomangiopericytoma) and oncogenic osteomalacia.
- Author
-
Brandwein-Gensler M and Siegal GP
- Subjects
- Aged, Diagnosis, Differential, Familial Hypophosphatemic Rickets metabolism, Female, Hemangiopericytoma metabolism, Hemangiopericytoma therapy, Humans, Meningeal Neoplasms pathology, Nasopharyngeal Neoplasms metabolism, Nasopharyngeal Neoplasms therapy, Osteomalacia metabolism, Solitary Fibrous Tumor, Pleural pathology, Familial Hypophosphatemic Rickets pathology, Hemangiopericytoma pathology, Nasopharyngeal Neoplasms pathology, Osteomalacia pathology
- Abstract
Sinonasal hemangiopericytoma-like tumors(SNHPC)(glomangiopericytomas)were originally conceived as histologically similar to, but biologically distinct from, their soft tissue counterparts. Re-evaluation of "hemangiopericytiomas" has determined that SNHPC (glomangiopericytomas) represent bona-fide pericyte-derived tumors, whereas most soft tissue neoplasms previously designated as hemangiopericytomas represent cellular variants of solitary fibrous tumors or other lesions with a hemangiopericytomalike growth pattern. We present an interesting case of a woman with SNHPC (glomangiopericytomas) causing oncogenic osteomalacia, and discuss the recent advances in our understanding of phosphaturic mesenchymal tumors. This particular case is an example of "Striking Pathology Gold"-a situation where the pathologist actively guides the diagnostic process, and witnesses its repercussions. "Striking Pathology Gold" may be a rare event in one's career. However it serves to remind us of our place in the world as physicians. Working behind the scenes, we quietly change the course of countless individual destinies for the better.
- Published
- 2012
- Full Text
- View/download PDF
31. Osteomalacia and insufficiency fracture in a hemodialysis patient with autosomal dominant polycystic kidney disease.
- Author
-
Hiramatsu R, Ubara Y, Suwabe T, Sumida K, Hayami N, Yamanouchi M, Mise K, Hasegawa E, Hoshino J, Sawa N, and Takaichi K
- Subjects
- Chronic Kidney Disease-Mineral and Bone Disorder etiology, Female, Humans, Hydroxycholecalciferols therapeutic use, Kidney Failure, Chronic complications, Kidney Failure, Chronic therapy, Malnutrition complications, Middle Aged, Osteomalacia pathology, Osteomalacia therapy, Polycystic Kidney, Autosomal Dominant therapy, Renal Dialysis, Vitamin D Deficiency etiology, Fractures, Stress etiology, Osteomalacia etiology, Polycystic Kidney, Autosomal Dominant complications
- Abstract
A 61-year-old Japanese woman on hemodialysis with autosomal dominant polycystic kidney disease (ADPKD) was admitted to the hospital with gluteal pain. Radiographs demonstrated a fracture of the left pubis. The serum 1,25(OH)(2)-vitamin D and 25(OH)-vitamin D levels were low. A biopsy of the right iliac crest disclosed osteomalacia. Active vitamin D sterol was administered in conjunction with dietary modification. Her gluteal pain was resolved three years later, and healing of the fracture was confirmed by radiology. This case emphasizes that vitamin D deficiency and malnutrition can cause osteomalacia in dialysis patients, even if calcium (Ca) and phosphate (P) levels are controlled by calcium carbonate.
- Published
- 2012
- Full Text
- View/download PDF
32. Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws?
- Author
-
Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Tregnago P, Valenti MT, Bertoldo F, Ferronato G, Nocini PF, Blandamura S, and Dalle Carbonare L
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Bisphosphonate-Associated Osteonecrosis of the Jaw pathology, Bone Density Conservation Agents therapeutic use, Calcification, Physiologic drug effects, Diphosphonates therapeutic use, Female, Humans, Male, Middle Aged, Risk Factors, Bisphosphonate-Associated Osteonecrosis of the Jaw complications, Bone Density Conservation Agents toxicity, Diphosphonates toxicity, Osteomalacia chemically induced, Osteomalacia complications, Osteomalacia pathology
- Abstract
Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ., Methods: This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%., Results: In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair., Conclusions: Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.
- Published
- 2012
- Full Text
- View/download PDF
33. Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature.
- Author
-
Hu FK, Yuan F, Jiang CY, Lv DW, Mao BB, Zhang Q, Yuan ZQ, and Wang Y
- Subjects
- Bone Neoplasms blood, Bone Neoplasms complications, Bone Neoplasms diagnostic imaging, Bone Neoplasms surgery, Female, Fibroblast Growth Factor-23, Follow-Up Studies, Humans, Hypophosphatemia blood, Hypophosphatemia diagnostic imaging, Hypophosphatemia etiology, Hypophosphatemia pathology, Hypophosphatemia surgery, Mesenchymoma blood, Mesenchymoma complications, Mesenchymoma diagnostic imaging, Mesenchymoma surgery, Middle Aged, Neoplasms, Connective Tissue blood, Neoplasms, Connective Tissue complications, Neoplasms, Connective Tissue diagnostic imaging, Neoplasms, Connective Tissue surgery, Osteomalacia blood, Osteomalacia diagnostic imaging, Osteomalacia etiology, Osteomalacia surgery, Paraneoplastic Syndromes, Phosphates blood, Radiography, Bone Neoplasms pathology, Fibroblast Growth Factors blood, Mesenchymoma pathology, Metacarpal Bones, Neoplasms, Connective Tissue pathology, Osteomalacia pathology
- Abstract
Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.
- Published
- 2011
- Full Text
- View/download PDF
34. Tumor-induced osteomalacia.
- Author
-
Chong WH, Molinolo AA, Chen CC, and Collins MT
- Subjects
- Algorithms, Animals, Diagnosis, Differential, Fibroblast Growth Factor-23, Fibroblast Growth Factors blood, Fibroblast Growth Factors metabolism, Fibroblast Growth Factors physiology, Humans, Neoplasms complications, Neoplasms pathology, Neoplasms therapy, Neoplasms, Connective Tissue pathology, Osteomalacia diagnosis, Osteomalacia etiology, Osteomalacia pathology, Osteomalacia therapy, Paraneoplastic Syndromes, Phosphates metabolism, Phosphates physiology, Neoplasms, Connective Tissue diagnosis, Neoplasms, Connective Tissue etiology, Neoplasms, Connective Tissue therapy
- Abstract
Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed.
- Published
- 2011
- Full Text
- View/download PDF
35. Development of osteomalacic myopathy in a morbidly obese woman following bariatric surgery.
- Author
-
Georgoulas TI, Tournis S, and Lyritis GP
- Subjects
- Bariatric Surgery methods, Female, Humans, Middle Aged, Muscle Weakness diagnosis, Muscle Weakness etiology, Muscle Weakness surgery, Muscular Diseases pathology, Muscular Diseases surgery, Osteomalacia diagnosis, Osteomalacia pathology, Osteomalacia surgery, Pain etiology, Pain surgery, Bariatric Surgery adverse effects, Muscular Diseases diagnosis, Obesity, Morbid surgery
- Published
- 2010
36. Photoclinic. Oncogenic osteomalacia.
- Author
-
Dehghani M, Dabaghmanesh MH, and Omrani GH
- Subjects
- Absorptiometry, Photon methods, Biopsy, Needle, Bone Density physiology, Follow-Up Studies, Humans, Immunohistochemistry, Magnetic Resonance Imaging methods, Male, Middle Aged, Osteomalacia pathology, Pain, Intractable diagnosis, Pain, Intractable etiology, Paraneoplastic Syndromes pathology, Risk Assessment, Severity of Illness Index, Tomography, X-Ray Computed methods, Bone Marrow pathology, Diagnostic Imaging methods, Osteomalacia diagnosis, Paraneoplastic Syndromes diagnosis
- Published
- 2010
37. A 61-year-old woman with osteomalacia and a thoracic spine lesion.
- Author
-
Marshall AE, Martin SE, Agaram NP, Chen JH, Horn EM, Douglas-Akinwande AC, and Hattab EM
- Subjects
- Diagnosis, Differential, Female, Humans, Magnetic Resonance Imaging, Middle Aged, Neoplasms, Complex and Mixed complications, Neoplasms, Complex and Mixed diagnosis, Neoplasms, Complex and Mixed pathology, Neoplasms, Connective Tissue complications, Neoplasms, Connective Tissue diagnosis, Neoplasms, Connective Tissue pathology, Osteomalacia complications, Spinal Neoplasms complications, Osteomalacia diagnosis, Osteomalacia pathology, Spinal Neoplasms diagnosis, Spinal Neoplasms pathology, Thoracic Vertebrae
- Abstract
Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) is a rare, largely benign, mesenchymal neoplasm almost invariably associated with oncogenic osteomalacia. It is generally found in the soft tissue and bone of the extremities. We report a case of a 61-year-old female with long-standing osteomalacia who was found to have PMT-MCT of the thoracic spine. There have been very few previously reported cases of PMT involving the spinal vertebrae and neuropathologists should be aware of this lesion. Recognition of PMT-MCT is critical for optimal patient care since complete surgical resection without additional therapy is curative.
- Published
- 2010
- Full Text
- View/download PDF
38. Renal phosphate wasting due to tumor-induced osteomalacia: a frequently delayed diagnosis.
- Author
-
Gore MO, Welch BJ, Geng W, Kabbani W, Maalouf NM, Zerwekh JE, Moe OW, and Sakhaee K
- Subjects
- Biopsy, Delayed Diagnosis, Female, Humans, Ilium pathology, Middle Aged, Osteomalacia etiology, Osteomalacia pathology, Hypophosphatemia complications, Neoplasms, Connective Tissue complications, Nose Neoplasms complications, Osteomalacia diagnosis
- Published
- 2009
- Full Text
- View/download PDF
39. Oncogenous osteomalacia.
- Author
-
Ghosh S, Sinha R, Bandyopadhyay R, and Malhotra M
- Subjects
- Hemangiopericytoma complications, Hemangiopericytoma pathology, Humans, Hypophosphatemia, Familial complications, Hypophosphatemia, Familial pathology, Male, Middle Aged, Paraneoplastic Syndromes complications, Paraneoplastic Syndromes pathology, Soft Tissue Neoplasms complications, Soft Tissue Neoplasms pathology, Treatment Outcome, Osteomalacia pathology, Osteomalacia surgery
- Abstract
Oncogenous osteomalacia is a rare paraneoplastic renal phosphaturic condition, often associated with highly vascular benign mesenchymal tumors. We report a case of a 48-year-old male who presented with debilitating osteomalacia unresponsive to standard therapy. Two years later, sinonasal hemangiopericytoma was diagnosed; the patient underwent complete surgical excision with rapid symptomatic improvement.
- Published
- 2009
- Full Text
- View/download PDF
40. Osteomalacia and vitamin D deficiency in the elderly.
- Author
-
Sitta Mdo C, Cassis SV, Horie NC, Moyses RM, Jorgetti V, and Garcez-Leme LE
- Subjects
- Diagnosis, Differential, Female, Humans, Middle Aged, Osteomalacia diagnostic imaging, Osteomalacia pathology, Radionuclide Imaging, Vitamin D Deficiency diagnostic imaging, Vitamin D Deficiency pathology
- Published
- 2009
- Full Text
- View/download PDF
41. Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype.
- Author
-
Bai X, Dinghong Q, Miao D, Goltzman D, and Karaplis AC
- Subjects
- Acid Phosphatase blood, Alkaline Phosphatase blood, Animals, Blotting, Northern, Calcitriol blood, Calcium blood, Crosses, Genetic, Female, Fibroblast Growth Factor-23, Fibroblast Growth Factors blood, Fibroblast Growth Factors genetics, Glucuronidase genetics, Glucuronidase metabolism, Immunohistochemistry, Isoenzymes blood, Klotho Proteins, Male, Mice, Mice, Knockout, Mice, Transgenic, Osteomalacia blood, Osteomalacia genetics, Osteomalacia pathology, Parathyroid Hormone blood, Phenotype, Phosphorus blood, Tartrate-Resistant Acid Phosphatase, Bone Remodeling physiology, Fibroblast Growth Factors metabolism, Glucuronidase deficiency, Osteomalacia metabolism
- Abstract
Transgenic mice overexpressing fibroblast growth factor (FGF23) (R176Q) (F(Tg)) exhibit biochemical {hypophosphatemia, phosphaturia, abnormal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] metabolism} and skeletal (rickets and osteomalacia) abnormalities attributable to FGF23 action. In vitro studies now implicate the aging-related factor Klotho in the signaling mechanism of FGF23. In this study, we used a mouse genetic approach to validate in vivo the pivotal role of Klotho in the metabolic and skeletal derangements associated with FGF23 (R176Q) overexpression. To this end, we crossed mice heterozygous for the hypomorphic Klotho allele (Kl(+/-)) to F(Tg) mice and obtained F(Tg) transgenic mice homozygous for the Kl-hypomorphic allele (F(Tg)/Kl(-/-)). Mice were killed on postnatal day 50, and serum and tissues were procured for analysis and comparison with F(Tg), wild-type, and Kl(-/-) controls. From 4 wk onward, F(Tg)/Kl(-/-) mice were clearly distinguishable from F(Tg) mice and exhibited a striking phenotypic resemblance to the Kl(-/-) controls. Serum analysis for calcium, phosphorus, parathyroid hormone, 1,25(OH)(2)D(3), and alkaline phosphatase activity confirmed the biochemical similarity between the F(Tg)/Kl(-/-) and Kl(-/-) mice and their distinctness from the F(Tg) controls. The characteristic skeletal changes associated with FGF23 (R176Q) overexpression were also dramatically reversed by the absence of Klotho. Hence the wide, unmineralized growth plates and the osteomalacic abnormalities apparent in trabecular and cortical bone were completely reversed in the F(Tg)/Kl(-/-) mice. Nevertheless, independent actions of Klotho on bone were suggested as manifested by alterations in mineralized bone, and in cortical bone volume which were observed in both the Kl(-/-) and F(Tr)/Kl(-/-) mutants. In summary, our findings substantiate in vivo the essential role of Klotho in the mechanism of action of FGF23 in view of the fact that Klotho ablation converts the biochemical and skeletal manifestations resulting from FGF23 overexpression to a phenotype consistent with Klotho deficiency.
- Published
- 2009
- Full Text
- View/download PDF
42. Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in Hyp mice.
- Author
-
Liu S, Tang W, Zhou J, Vierthaler L, and Quarles LD
- Subjects
- Age Factors, Animals, Bone Density, Bone Transplantation methods, Cartilage, Articular metabolism, Cartilage, Articular pathology, Disease Models, Animal, Familial Hypophosphatemic Rickets blood, Familial Hypophosphatemic Rickets pathology, Female, Femur transplantation, Fibroblast Growth Factor-23, Fibroblast Growth Factors blood, Fibroblast Growth Factors genetics, Gene Expression Regulation, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Growth Plate metabolism, Growth Plate pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Osteomalacia genetics, Osteomalacia pathology, Promoter Regions, Genetic genetics, Tibia transplantation, Calcification, Physiologic physiology, Familial Hypophosphatemic Rickets metabolism, Fibroblast Growth Factors metabolism, Genetic Diseases, X-Linked, Osteocytes metabolism, PHEX Phosphate Regulating Neutral Endopeptidase genetics
- Abstract
X-linked hypophosphatemia (XLH) is characterized by hypophosphatemia and impaired mineralization caused by mutations of the PHEX endopeptidase (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), which leads to the overproduction of the phosphaturic fibroblast growth factor 23 (FGF23) in osteocytes. The mechanism whereby PHEX mutations increase FGF23 expression and impair mineralization is uncertain. Either an intrinsic osteocyte abnormality or unidentified PHEX substrates could stimulate FGF23 in XLH. Similarly, impaired mineralization in XLH could result solely from hypophosphatemia or from a concomitant PHEX-dependent intrinsic osteocyte abnormality. To distinguish between these possibilities, we assessed FGF23 expression and mineralization after reciprocal bone cross-transplantations between wild-type (WT) mice and the Hyp mouse model of XLH. We found that increased FGF23 expression in Hyp bone results from a local effect of PHEX deficiency, since FGF23 was increased in Hyp osteocytes before and after explantation into WT mice but was not increased in WT osteocytes after explantation into Hyp mice. WT bone explanted into Hyp mice developed rickets and osteomalacia, but Hyp bone explanted into WT mice displayed persistent osteomalacia and abnormalities in the primary spongiosa, indicating that both phosphate and PHEX independently regulate extracellular matrix mineralization. Unexpectedly, we observed a paradoxical suppression of FGF23 in juvenile Hyp bone explanted into adult Hyp mice, indicating the presence of an age-dependent systemic inhibitor of FGF23. Thus PHEX functions in bone to coordinate bone mineralization and systemic phosphate homeostasis by directly regulating the mineralization process and producing FGF23. In addition, systemic counterregulatory factors that attenuate the upregulation of FGF23 expression in Hyp mouse osteocytes are present in older mice.
- Published
- 2007
- Full Text
- View/download PDF
43. Imaging of oncogenic osteomalacia.
- Author
-
Gershinsky M, Croitoru S, Dickstein G, Bardicef O, Gelman R, and Barmeir E
- Subjects
- Alkaline Phosphatase blood, Female, Humans, Hypophosphatemia etiology, Ischium pathology, Mesenchymoma surgery, Middle Aged, Soft Tissue Neoplasms surgery, Magnetic Resonance Imaging, Mesenchymoma diagnosis, Osteomalacia etiology, Osteomalacia pathology, Soft Tissue Neoplasms diagnosis
- Published
- 2007
44. Oncogenic osteomalacia: exact tumor localization by co-registration of positron emission and computed tomography.
- Author
-
Hesse E, Moessinger E, Rosenthal H, Laenger F, Brabant G, Petrich T, Gratz KF, and Bastian L
- Subjects
- Bone Neoplasms pathology, Female, Gallium Radioisotopes, Humans, Middle Aged, Osteomalacia pathology, Positron-Emission Tomography, Tomography, X-Ray Computed, Bone Neoplasms diagnostic imaging, Osteomalacia diagnostic imaging
- Abstract
Unlabelled: In oncogenic osteomalacia, the causative tumor is almost always difficult to find. A novel diagnostic approach is presented that facilitates a precise and rapid localization of the associated lesion by PET-CT co-registration using the radiotracer (68)Ga-DOTANOC., Introduction: Oncogenic osteomalacia (OOM) is an uncommon disorder characterized by hyperphosphaturia, hypophosphatemia, decreased vitamin D(3) serum levels, and osteomalacia. The paraneoplastic syndrome is exclusively driven by a small somatostatin receptor (sst)-positive tumor that produces phosphatonins, proteins that cause renal phosphate loss. OOM can be cured completely on tumor removal. However, the exact tumor localization is the most challenging step, because the lesion is notoriously difficult to detect by common imaging techniques., Materials and Methods: A 60-year-old woman complained of severe pain in her back and chest wall, muscle weakness, and reduced physical activity for >1 year. She suffered a metatarsal fracture and presented with hyperphosphaturia and hypophosphatemia. OOM was suspected, and a meticulous search for the tumor was initiated by conventional imaging techniques, sst-mediated imaging using (111)In-octreotide scintigraphy, and (68)Ga-DOTANOC-based positron emission tomography (PET)-CT co-registration. (68)Ga-DOTANOC is a novel radiopharmaceutical compound in which the somatostatin analog octreotide is modified at position 3, chelated with DOTA, and complexed with (68)Gallium. (68)Ga-DOTANOC has an improved affinity to sst2 and sst5 relative to other radiopeptides., Results: Whereas common imaging techniques such as CT failed to localize the tumor, (111)In-octreotide scintigraphy was able to detect the lesion, but only PET-CT using (68)Ga-DOTANOC revealed the exact tumor localization in the right femoral head. On tumor resection, the well being of the patient improved significantly, and biochemical parameters returned to normal., Conclusions: (68)Ga-DOTANOC-based PET-CT is a novel and powerful approach to detect sst-positive tumors in a timely manner and to provide highly resolved images facilitating the development of a therapeutic strategy.
- Published
- 2007
- Full Text
- View/download PDF
45. Treatment of Kienböck's disease with cultured stem cell-seeded hybrid tendon roll interposition arthroplasty: experimental study.
- Author
-
Shigematsu K, Hattori K, Kobata Y, Kawamura K, Yajima H, and Takakura Y
- Subjects
- Animals, Biopsy, Needle, Cells, Cultured, Disease Models, Animal, Female, Immunohistochemistry, Lunate Bone diagnostic imaging, Male, Osteomalacia pathology, Rabbits, Radiography, Risk Factors, Sensitivity and Specificity, Stem Cell Transplantation, Arthroplasty methods, Lunate Bone surgery, Osteomalacia surgery, Tendon Transfer methods, Tissue Engineering
- Abstract
Background: Several procedures that consist of excision arthroplasty, intercarpal arthrodesis with or without excision of the lunate, proximal row carpectomy, and joint leveling procedures are used to treat advanced Kienböck's disease. However, no reconstructive surgery for a collapsed lunate has been established. The aim of this study was to develop a method of tendon roll interposition arthroplasty using a tissue-engineering technique to improve the clinical results of the tendon roll interposition arthroplasty for treating advanced Kienböck's disease., Methods: Twenty-four Japanese white rabbits were used for this study as three treatment models of Kienböck's disease. The lunate of the right paw was excised, and then one of three kinds of tendon roll was interposed into the excision space as follows: group A (controls), a conventional tendon roll made of autologous Achilles tendon; group B (cored tendon roll) a tendon roll with a core of the collagen-ceramic composite; and group C (hybrid tendon roll), a scaffold seeded with cultured cells was rolled in the Achilles tendon. In all groups the right wrist was immobilized with cast 6 weeks after surgery. Wrist radiography was evaluated 0, 4, 6, and 12 weeks after surgery; specimens were sectioned and evaluated histologically 12 weeks after surgery., Results: In group C the small shadow of the hydroxyapatite granule gradually increased until 12 weeks after surgery, whereas in group B the shadow of the core gradually decreased. The deficit spaces of the lunate remained radiographically lucent for 12 weeks after surgery in group A. Histological findings revealed new bone formation at the center and stained cartilage matrix at the peripheral of the hybrid tendon roll group (group C) but not in group A or B., Conclusions: Radiological and histological examinations proved that it is possible to make new hybrid tendon rolls using this method, as osteogenesis in the center and cartilage matrix in the peripheral of the tendon roll were revealed.
- Published
- 2006
- Full Text
- View/download PDF
46. DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis.
- Author
-
Ling Y, Rios HF, Myers ER, Lu Y, Feng JQ, and Boskey AL
- Subjects
- Animals, Bone Density genetics, Bone Matrix chemistry, Calcification, Physiologic genetics, Calcium blood, Collagen chemistry, Crystallization, Diaphyses pathology, Extracellular Matrix Proteins genetics, Female, Heterozygote, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteomalacia genetics, Osteomalacia pathology, Phosphates blood, Phosphoproteins genetics, Spectroscopy, Fourier Transform Infrared, Tibia chemistry, Tibia pathology, Calcification, Physiologic physiology, Extracellular Matrix Proteins physiology, Phosphoproteins physiology
- Abstract
Unlabelled: The role of DMP1 in mineralization was analyzed by comparing bone mineral and matrix properties in dmp1-null female mice to heterozygous and wildtype controls by FTIR imaging spectroscopy. The observed decreased mineral content in dmp1 null mice indicates a key role for dmp1 in bone mineralization. Indirect effects of DMP1 on other systems also determine the KO phenotype., Introduction: Dentin matrix protein 1 (DMP1), an acidic phosphorylated extracellular matrix protein, is highly expressed in mineralized tissues. In vitro, DMP1 peptides can promote or inhibit mineralization depending on the extent of phosphorylation, the peptide size, and concentration. To clarify the biological function of DMP1 protein on in vivo mineralization, this study analyzed bone properties of dmp1 knockout (KO) mice compared with heterozygous (HET) and wildtype (WT) controls., Materials and Methods: Tibias from dmp1 KO and age-, sex-, and background-matched HET and WT mice at 4 and 16 weeks (N(total) = 60) were examined by Fourier transform infrared imaging (FTIRI), histology (n = 6 per genotype and age; N = 36), and geometry by muCT (n = 4 per genotype and age; N = 24). Serum ionic calcium and phosphate concentrations were also determined., Results: The mineral-to-matrix ratios (spectroscopic parameter of relative mineral content) were significantly lower in dmp1 KO mice tibias compared with WT and HET at 4 and 16 weeks. The mineral crystallinity (crystal size/perfection) was significantly increased in dmp1 KO and HET mice relative to WT. Collagen cross-link ratios (a spectroscopic parameter related to the relative amounts of nonreducible/reducible collagen cross-links) in dmp1 KO were not significantly different from WT and HET. Based on muCT, cortical bone cross-sectional areas at 16 but not 4 weeks were significantly reduced in the KO compared with controls. Maximum, minimum, and polar cross-sectional moments of inertia were significantly lower in dmp1 KO than in HET at 16 weeks but not at 4 weeks. Histological analysis and muCT 3-D images suggested that dmp1 KO mice had osteomalacia. Dmp1 KO mice had significantly lower ionic calcium and phosphate concentrations relative to WT, whereas in the HET, values for phosphate were equivalent, and calcium values were decreased relative to WT values., Conclusions: The findings of decreased mineral-to-matrix ratio and increased crystal size in bones of dmp1 KO mice suggest that DMP1 has multiple roles (both direct and indirect) in the regulation of postnatal mineralization. We suggest that direct effects on mineral formation, crystal growth, and indirect effects on regulation of Ca x P concentrations and matrix turnover all contribute to the dominant phenotype in the dmp1 KO mouse.
- Published
- 2005
- Full Text
- View/download PDF
47. Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders.
- Author
-
Bai X, Miao D, Li J, Goltzman D, and Karaplis AC
- Subjects
- Animals, Bone and Bones pathology, Bone and Bones physiopathology, Calcium blood, Carcinoma, Hepatocellular, Cell Line, Tumor, Female, Fibroblast Growth Factor-23, Fibroblast Growth Factors blood, Gene Expression, Humans, Hypophosphatemia, Familial blood, Hypophosphatemia, Familial pathology, Kidney Tubules, Proximal physiopathology, Male, Mice, Mice, Transgenic, Osteomalacia blood, Osteomalacia pathology, Parathyroid Hormone blood, Phosphates blood, Pregnancy, Vitamin D blood, Fibroblast Growth Factors genetics, Hypophosphatemia, Familial physiopathology, Osteomalacia physiopathology, Parathyroid Hormone physiology
- Abstract
Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D(3)) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D(3) production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.
- Published
- 2004
- Full Text
- View/download PDF
48. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis.
- Author
-
Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Jüppner H, and Jonsson KB
- Subjects
- Animals, Bone and Bones pathology, Bone and Bones physiology, Calcification, Physiologic, Calcium blood, Calcium urine, Fibroblast Growth Factor-23, Growth Disorders pathology, Growth Disorders physiopathology, Homeostasis physiology, Humans, Kidney cytology, Kidney physiology, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Osteomalacia pathology, Osteomalacia physiopathology, Parathyroid Glands pathology, Parathyroid Glands physiology, Phenotype, Phosphates urine, Promoter Regions, Genetic, Vitamin D metabolism, Collagen Type I genetics, Fibroblast Growth Factors genetics, Fibroblast Growth Factors metabolism, Growth Disorders metabolism, Osteomalacia metabolism, Phosphates blood
- Abstract
Mutations in the fibroblast growth factor 23 gene, FGF23, cause autosomal dominant hypophosphatemic rickets (ADHR). The gene product, FGF-23, is produced by tumors from patients with oncogenic osteomalacia (OOM), circulates at increased levels in most patients with X-linked hypophosphatemia (XLH) and is phosphaturic when injected into rats or mice, suggesting involvement in the regulation of phosphate (Pi) homeostasis. To better define the precise role of FGF-23 in maintaining Pi balance and bone mineralization, we generated transgenic mice that express wild-type human FGF-23, under the control of the alpha1(I) collagen promoter, in cells of the osteoblastic lineage. At 8 wk of age, transgenic mice were smaller (body weight = 17.5 +/- 0.57 vs. 24.3 +/- 0.37 g), exhibited decreased serum Pi concentrations (1.91 +/- 0.27 vs. 2.75 +/- 0.22 mmol/liter) and increased urinary Pi excretion when compared with wild-type littermates. The serum concentrations of human FGF-23 (undetectable in wild-type mice) was markedly elevated in transgenic mice (>7800 reference units/ml). Serum PTH levels were increased in transgenic mice (231 +/- 62 vs. 139 +/- 44 pg/ml), whereas differences in calcium and 1,25-dihydroxyvitamin D were not apparent. Expression of Npt2a, the major renal Na(+)/Pi cotransporter, as well as Npt1 and Npt2c mRNAs, was significantly decreased in the kidneys of transgenic mice. Histology of tibiae displayed a disorganized and widened growth plate and peripheral quantitative computerized tomography analysis revealed reduced bone mineral density in transgenic mice. The data indicate that FGF-23 induces phenotypic changes in mice resembling those of patients with ADHR, OOM, and XLH and that FGF-23 is an important determinant of Pi homeostasis and bone mineralization.
- Published
- 2004
- Full Text
- View/download PDF
49. Iron lactate-induced osteomalacia in association with osteoblast dynamics.
- Author
-
Matsushima S, Torii M, Ozaki K, and Narama I
- Subjects
- Administration, Oral, Animals, Diet, Disease Models, Animal, Iron Compounds administration & dosage, Iron Compounds analysis, Lactates administration & dosage, Male, Osteoblasts pathology, Osteocalcin blood, Osteomalacia blood, Osteomalacia pathology, Parathyroid Hormone blood, Phosphorus blood, Rats, Rats, Sprague-Dawley, Tibia drug effects, Tibia pathology, Iron Compounds toxicity, Lactates toxicity, Osteoblasts drug effects, Osteogenesis drug effects, Osteomalacia chemically induced
- Abstract
Osteomalacia was induced in rats fed a diet containing 50,000 ppm (5%) iron lactate for 13 weeks. The histopathology and histomorphometrical dynamics of osteoblasts under this condition were examined. Bone histomorphometry of the proximal tibial metaphysis revealed that the osteoblast surface, osteoid volume, osteoid surface and labeled surface ratio, which are the parameters of bone formation had increased. The blood chemistry revealed the greatest elevation in the osteocalcin level; however, the parathyroid hormone (PTH) secretion and inorganic phosphorus level were very low. From the serum biochemical, histopathological and histomorphometrical findings, the bone lesion in iron lactate-overloaded rats was considered to be similar to low turnover osteomalacia showing decreased trabeculae in secondary spongiosa and increased lamellar osteoid. Furthermore, an iron-positive reaction was detected at the interface between osteoid and mineralized bone. In the bone lesions induced by chronic iron overload, osteoblast recruitment exceeded that of mineralization or, alternatively, the iron within osteoblasts along the trabecular bone suppressed the remodeling and led to an increase in osteoid thickness.
- Published
- 2003
- Full Text
- View/download PDF
50. Bone histomorphometry in children and adolescents with beta-thalassemia disease: iron-associated focal osteomalacia.
- Author
-
Mahachoklertwattana P, Sirikulchayanonta V, Chuansumrit A, Karnsombat P, Choubtum L, Sriphrapradang A, Domrongkitchaiporn S, Sirisriro R, and Rajatanavin R
- Subjects
- Adipose Tissue pathology, Adipose Tissue physiology, Adolescent, Body Composition physiology, Bone Density, Bone Development physiology, Bone and Bones metabolism, Child, Ferritins metabolism, Hormones blood, Humans, Iron metabolism, Osteomalacia metabolism, beta-Thalassemia metabolism, Bone and Bones pathology, Iron physiology, Osteomalacia pathology, beta-Thalassemia pathology
- Abstract
Thalassemia/hemoglobinopathy is a hereditary disease that causes chronic anemia and increased erythropoiesis. Consequently, an expansion of bone marrow spaces may contribute to osteopenia/osteoporosis. However, the pathogenesis of bone changes is not yet known. We, therefore, carried out the study on bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease with the hope of gaining some new insight into the cellular and structural alterations of thalassemic bone. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Bone mineral density (BMD) measurements were performed by dual energy x-ray absorptiometry. Most patients had growth retardation and delayed bone age. BMD was low especially at the lumbar spine. Serum IGF-I levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. Moreover, focal thickened osteoid seams were found together with focal iron deposits. Dynamic bone formation study revealed reduced bone formation rate. These findings indicate that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. Iron deposits in bone and low circulating IGF-I levels may partly contribute to the above findings.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.