637 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. Histomorphometric analysis of patients with femoral neck fracture and 25-hydroxyvitamin D deficiency: a cross-sectional study.
- Author
-
Okumura G, Yamamoto N, Suzuki H, Ninomiya H, Hirano Y, Tei Y, Tomiyama Y, Shimakura T, Takahashi HE, Imai N, and Kawashima H
- Subjects
- Humans, Cross-Sectional Studies, Bone Density, Calcifediol, Femur Head pathology, Osteomalacia pathology, Vitamin D analogs & derivatives, Osteoporosis, Vitamin D Deficiency complications, Femoral Neck Fractures
- Abstract
Introduction: Vitamin D deficiency causes osteoporosis, bone mineralization disorders, and osteomalacia. Osteomalacia is diagnosed using blood biochemical tests, clinical symptoms, and imaging; however, accurate detection of mineralization disorders requires tissue observation. We investigated the prevalence of bone mineralization disorders and their relationship with serum 25-hydroxyvitamin D (25OHD) levels in patients with untreated osteoporosis with femoral neck fractures., Materials and Methods: A non-demineralized specimen was prepared from the femoral head removed during surgery in 65 patients. Bone histomorphometry of cancerous bone in the femoral head center was conducted. Osteoid volume per bone volume (OV/BV) and osteoid thickness (O.Th) were measured as indicators of mineralization disorder., Results: The mean serum 25OHD level (11.9 ± 5.7 ng/mL) was in the deficiency range (< 12 ng/mL). There were no clinically diagnosed cases of osteomalacia (OV/BV > 10% and O.Th > 12.5 µm); however, one case of mineralization disorder, considered histologically pre-osteomalacia (OV/BV > 5% and O.Th < 12.5 µm), was observed (OB/BV, 17.6%; O.Th, 12.3 µm). Excluding this case, those with severe (25OHD < 12 ng/mL, at risk of osteomalacia; n = 39) and non-severe deficiency (25OHD ≥ 12 ng/mL; n = 25) did not significantly differ in OV/BV (%; 0.77 ± 0.54 vs. 0.69 ± 0.38, p = 0.484) or O.Th (µm; 5.32 ± 1.04 vs. 5.13 ± 0.78, p = 0.410). Further, 25OHD and OV/BV were not significantly correlated (R = - 0.124, p = 0.327)., Conclusion: This is the first study in the twenty-first century to examine serum 25OHD concentrations and bone mineralization disorders in Japanese patients with osteoporosis. The results indicate that vitamin D deficiency does not necessarily cause bone mineralization disorders and rarely leads to osteomalacia., (© 2024. The Japanese Society Bone and Mineral Research.)
- Published
- 2024
- Full Text
- View/download PDF
4. Tumor-induced osteomalacia: An overview.
- Author
-
Jadhav SS, Shah R, and Patil V
- Subjects
- Humans, Neoplasms, Connective Tissue diagnosis, Neoplasms, Connective Tissue etiology, Neoplasms, Connective Tissue therapy, Osteomalacia etiology, Osteomalacia diagnosis, Osteomalacia pathology, Mesenchymoma complications, Mesenchymoma diagnosis, Mesenchymoma pathology, Paraneoplastic Syndromes diagnosis, Paraneoplastic Syndromes etiology, Paraneoplastic Syndromes pathology
- Abstract
Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
5. Skeletal Perturbations Following Sudden Stimuli.
- Author
-
Minisola S, Colangelo L, Pepe J, and Cipriani C
- Subjects
- Humans, Calcium, Bone and Bones pathology, Calcium, Dietary, Osteomalacia pathology, Paraneoplastic Syndromes
- Published
- 2024
- Full Text
- View/download PDF
6. 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
7. 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
8. Osteomalacia Prevalence, Biochemical Profile, and Histology in Patients with Low-Energy Hip Fractures Over the Age of 45.
- Author
-
Mirghaderi P, Mortezaei A, Parry JA, Salimi M, Mirghaderi R, Moharrami A, and Mortazavi SMJ
- Subjects
- Aged, Humans, Cross-Sectional Studies, Ilium pathology, Ilium surgery, Prevalence, Middle Aged, Biopsy, Aged, 80 and over, Male, Female, Biomarkers blood, Biomarkers urine, Blood Chemical Analysis standards, Sensitivity and Specificity, Hip Fractures complications, Osteomalacia complications, Osteomalacia diagnosis, Osteomalacia epidemiology, Osteomalacia pathology
- Abstract
Our objective was to determine the prevalence of osteomalacia in low-energy hip fracture patients over the age of 45, based on biochemical and histological measures. This cross-sectional study included 72 patients over 45 with low-energy mechanism hip fractures. Samples of fasting venous blood were taken for hemograms and serum biochemistry analyses. Bicortical biopsies of the iliac crest were obtained, processed, and evaluated by an expert pathologist for osteomalacia. Biochemical osteomalacia (b-OM) is defined according to a distinct criterion. A low level of serum calcium, phosphorus, albumin, and 25OHD was found in 43.1, 16.7, 73.6, and 59.7% of patients, respectively. 50.0% of patients had high serum alkaline phosphatase (ALP) levels. b-OM was found in 30 (41.7%), and no significant association was found with PTH, Cr, Alb, age, sex, fracture type, side of the trauma, and season were not associated with osteomalacia. Osteomalacia was diagnosed on histopathological analysis in 19/72 (26.7%), and 54/72 (75.0%) of all cases fulfilled b-OM criteria. In the histologic evaluation, osteoid seam width, osteoid surface, and osteoid volume were 28.5 µm, 25.6, and 12.1%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the biochemical test for detecting osteomalacia were 73.6, 64.2, 42.4, 87.2, and 66.7%, respectively. Up to 30% of elderly patients with low-energy hip fractures are affected by osteomalacia. A biochemical screening along with a bone biopsy and histopathologic evaluation may be logical in a high-risk population for osteomalacia diagnosis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
9. Occipital bone and tumor-induced osteomalacia: a rare tumor site for an uncommon paraneoplastic syndrome.
- Author
-
Colangelo L, Sonato C, Cipriani C, Pepe J, Farinacci G, Palmisano B, Occhiuto M, Riminucci M, Corsi A, and Minisola S
- Subjects
- Male, Humans, Middle Aged, Neoplasms, Connective Tissue etiology, Neoplasms, Connective Tissue complications, Paraneoplastic Syndromes complications, Paraneoplastic Syndromes surgery, Osteomalacia etiology, Osteomalacia pathology, Hypophosphatemia etiology, Hypophosphatemia pathology, Hypophosphatemia surgery
- Abstract
Introduction: Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome due to the overproduction of fibroblast growth factor 23 (FGF23). It is predominantly caused by mesenchymal tumors and cured upon their complete removal. Non-surgical treatment is an alternative option but limited to specific clinical conditions., Methods: We report a challenging case of TIO caused by a tumor involving the occipital bone. We also performed a literature review of TIO caused by tumors localized at this site, focusing on clinical findings, treatment, and outcomes., Results: The patient, a 62-year-old male, presented with a long-lasting history of progressive weakness. Biochemical evaluation revealed severe hypophosphatemia due to low renal tubular reabsorption of phosphate with raised intact FGF23 values. A
68 Ga-DOTATATE PET/TC imaging showed a suspicious lesion located in the left occipital bone that MRI and selective venous catheterization confirmed to be the cause of TIO. Stereotactic gamma knife radiosurgery was carried out, but unfortunately, the patient died of acute respiratory failure. To date, only seven additional cases of TIO have been associated to tumors located in the occipital bone. Furthermore, the tumor involved the left side of the occipital bone in all these patients., Conclusion: The occipital region is a difficult area to access so a multidisciplinary approach for their treatment is required. If anatomical differences could be the basis for the predilection of the left side of the occipital bone, it remains to be clarified., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
10. Tumor induced osteomalacia from a peripheral mesenchymal tumour of the foot.
- Author
-
Strydom A, Greeff W, Ferrao PNF, and Saragas NP
- Subjects
- Humans, Fibroblast Growth Factors, Phosphates, Osteomalacia diagnosis, Osteomalacia etiology, Osteomalacia pathology, Paraneoplastic Syndromes diagnosis, Paraneoplastic Syndromes etiology, Paraneoplastic Syndromes pathology
- Abstract
Tumour induced osteomalacia (TIO) is a rare condition caused by peripheral mesenchymal tumours (PMT) which produce fibroblast-growth factor 23 (FGF23). FGF23 inhibits renal phosphate reabsorption leading to vitamin D resistant osteomalacia. The rarity of the condition and difficulty with isolating the PMT make diagnosis difficult, with delayed treatment leading to significant patient morbidity. We present a case of PMT of the foot with TIO, with a discussion on diagnosis and treatment., Competing Interests: Conflict of Interest Statement Each author certifies that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
11. Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases.
- Author
-
Bosman A, Palermo A, Vanderhulst J, De Beur SMJ, Fukumoto S, Minisola S, Xia W, Body JJ, and Zillikens MC
- Subjects
- Delayed Diagnosis adverse effects, Female, Fibroblast Growth Factors, Humans, Male, Hypophosphatemia, Osteomalacia diagnosis, Osteomalacia etiology, Osteomalacia pathology, Paraneoplastic Syndromes diagnosis
- Abstract
Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
12. Intracranial phosphaturic mesenchymal tumors. A case report and review of literature.
- Author
-
Kojima D, Ohba S, Abe M, Suzuki A, Horibe S, Tateya I, Hasegawa M, and Hirose Y
- Subjects
- Fibroblast Growth Factors genetics, Fibroblast Growth Factors metabolism, Humans, Male, Middle Aged, Neoplasm Recurrence, Local complications, Phosphates metabolism, Phosphorus metabolism, RNA, Messenger, STAT6 Transcription Factor metabolism, Vitamin D, Brain Neoplasms complications, Hemangiopericytoma, Hypophosphatemia etiology, Hypophosphatemia pathology, Mesenchymoma complications, Mesenchymoma surgery, Neoplasms, Connective Tissue diagnosis, Neoplasms, Connective Tissue pathology, Neoplasms, Connective Tissue surgery, Osteomalacia diagnosis, Osteomalacia etiology, Osteomalacia pathology, Soft Tissue Neoplasms complications
- Abstract
Most osteomalacia-inducing tumors (OITs) are phosphaturic mesenchymal tumors (PMTs) that secrete fibroblast growth factor 23 (FGF23). These tumors usually occur in the bone and soft tissues, and intracranial OITs are rare. Therefore, intracranial OIT is difficult to diagnose and treat. This paper presents a case of intracranial OIT and shows a review of previous cases. A 45-year-old man underwent nasal cavity biopsy and treatment with active vitamin D
3 and neutral phosphate for hypophosphatemia. Amplification of FGF23 mRNA level within the tumor was detected. Subsequently, the surgical specimen was diagnosed with a PMT and was considered the cause of the patient's osteomalacia. The patient was referred to a neurosurgery department for the excision of the intracranial tumor extending to the nasal cavity. After tumor removal, the serum levels of FGF23 and phosphorus were normalized as compared to preoperative those. The patient remains disease-free, without additional treatment, approximately 10 years after surgery, with no tumor recurrence. As per the literature, intracranial OITs usually occur in patients aged 8-69 years. Bone and muscle pain are major complaints. Approximately 60% of the patients reported previously had symptoms because of intracranial tumors. In some cases, it took several years to diagnose OIT after the onset of the osteomalacia symptoms. Laboratory data in such cases show hypophosphatemia and elevated FGF23 levels. Because FGF23 levels are associated with the severity of osteomalacia symptoms, total tumor resection is recommended. PMT and hemangiopericytoma (HPC) are histologically similar, but on immunochemistry, PMT is negative for signal transducer and activator of transcription 6 (STAT6), whereas HPC is positive. FGF23 amplification is seen in PMTs but not in HPCs. Therefore, the analysis of FGF23 and STAT6 was helpful in distinguishing PMTs from HPCs. In cases of hypophosphatemia and osteomalacia without a history of metabolic, renal, or malabsorptive diseases, the possibility of oncogenic osteomalacia should be considered., (© 2022 Japanese Society of Neuropathology.)- Published
- 2022
- Full Text
- View/download PDF
13. [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
14. Hypophosphatemia related to a neuro-endocrine tumor of the pancreas: A case report.
- Author
-
Pickering ME, Bouvier D, Puravet A, Soubrier M, Sapin V, and Oris C
- Subjects
- Aged, Calcitriol, Female, Fibroblast Growth Factors, Humans, Paraneoplastic Syndromes, Phosphates, Endocrine System Diseases, Hypophosphatemia etiology, Osteomalacia etiology, Osteomalacia metabolism, Osteomalacia pathology, Pancreatic Neoplasms complications
- Abstract
Background: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by hypophosphatemia associated with elevated fibroblast growth factor 23 (FGF23). TIO is primarily caused by benign mesenchymal tumors of the soft tissue and skeleton. Rarely, it is associated with a solid tumor or hematological malignancy. To date, no case of osteomalacia related to pancreatic cancer has been reported in the literature., Case Report: A 77-year-old woman was admitted to the rheumatology department (RD) of the Clermont-Ferrand University Hospital (France) for further evaluation of her hypophosphatemia. The patient reported bone pain, myalgia, and asthenia. Further laboratory tests revealed hyperphosphaturia, normocalcemia, low serum calcitriol, elevated serum alkaline phosphatase (ALP), and elevated plasma parathyroid hormone (PTH). A renal phosphate depletion disorder was suspected as an etiology for this hypophosphatemia. Finally, FGF23 levels were found to be significantly elevated, leading to a definitive diagnosis of pancreatic neuroendocrine tumor., Conclusion: This is the first report of hypophosphatemic osteomalacia related to pancreatic cancer. Therefore, in the setting of hypophosphatemia associated with renal phosphate wasting and low calcitriol level, plasma FGF23 measurement should be considered., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
15. 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
16. 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
17. Phosphaturic mesenchymal tumors: radiological aspects and suggested imaging pathway.
- Author
-
Hussein MAM, Cafarelli FP, Paparella MT, Rennie WJ, and Guglielmi G
- Subjects
- Humans, Mesenchymoma pathology, Osteomalacia pathology, Paraneoplastic Syndromes pathology, Diagnostic Imaging methods, Mesenchymoma diagnostic imaging, Osteomalacia diagnostic imaging, Paraneoplastic Syndromes diagnostic imaging
- Abstract
Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal neoplasms of soft tissue or bone origin that can give rise to a challenge in diagnostic imaging. These tumors are frequently associated with tumor-induced osteomalacia, also called oncogenic osteomalacia, which is a rare paraneoplastic syndrome characterized by ectopic secretion of fibroblast growth factor 23, a hormone that regulates serum phosphate level. PMTs show polymorphic features on both radiological findings and histological examination, causing problems in diagnosis owing to their similarity with other mesenchymal tumors. Thus, this paper aims to describe radiological aspects of PMTs and suggest an imaging pathway for accurate diagnosis throughout the evidence from the literature review., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
18. 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
19. Clinical, morphological and immunohistochemical analysis of 13 cases of phosphaturic mesenchymal tumor - A holistic diagnostic approach.
- Author
-
Chatterjee D, Bardia A, Pal R, Saikia UN, Bhadada SK, and Radotra BD
- Subjects
- Adult, Biomarkers, Tumor analysis, Female, Humans, Hypophosphatemia diagnosis, Hypophosphatemia metabolism, Hypophosphatemia pathology, Immunohistochemistry methods, Immunophenotyping methods, Male, Mesenchymoma diagnosis, Middle Aged, Osteomalacia diagnosis, Osteomalacia pathology, Paraneoplastic Syndromes diagnosis, Paraneoplastic Syndromes pathology, Retrospective Studies, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms metabolism, Mesenchymoma metabolism, Mesenchymoma pathology, Osteomalacia metabolism, Paraneoplastic Syndromes metabolism, Soft Tissue Neoplasms pathology
- Abstract
Background: Phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT) is a rare tumor characterized clinically by presence of tumor-induced osteomalacia (TIO), subsequent to elevated fibroblastic growth factor 23 (FGF23) levels. This study aims to analyse the morphological spectrum of PMT along with clinico-pathological correlation and immunophenotype profile of this rare tumor., Materials and Methods: Detailed histological analysis of all tumors presenting with TIO over past 7 years was done retrospectively. Immunohistochemistry was performed in all cases for SATB2, STAT6, CD34, FGF23, ERG, S100 and smooth muscle actin (SMA)., Results: A total of 13 cases were analysed (8 female and 5 male) with mean age of 39.8 years. Five cases were arising from bone while 4 each from soft tissue and nasal cavity/paranasal sinus. All presented with hypophosphatemia, hyperphosphaturia, elevated serum FGF23 and features suggestive of osteomalacia. Histological examination revealed basophilic 'grungy' calcification seen in 7 (53.8%), osteoid formation in 8 (61.5%), chondroid matrix in 4 (30.8%), adipose tissue in 6 (46.2%), osteoclast-like giant cells in 9 (69.2%) and hemangiopericytomatous (HPC like) blood vessels in 7 cases (53.8%). HPC like vessels and adipose tissue were more common in nasal tumors while calcification was more common in tumors arising from bone. All cases showed immunoreactivity for SATB2 and clinical improvement following resection except one case with residual tumor., Conclusion: PMT shows varied histological pattern with various matrix components depending on the site of the tumor. Serum FGF-23 is a useful adjunctive marker for diagnosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
20. Relationship between osteoid formation and iron deposition induced by chronic cadmium exposure in ovariectomized rats.
- Author
-
Wako Y, Hiratsuka H, Kurotaki T, Tsuchitani M, and Umemura T
- Subjects
- Animals, Cadmium administration & dosage, Female, Femur drug effects, Femur pathology, Osteomalacia pathology, Ovariectomy adverse effects, Rats, Rats, Sprague-Dawley, Cadmium toxicity, Iron metabolism, Osteomalacia chemically induced
- Abstract
Itai-itai (Japanese, "It hurts! It hurts!") disease (IID), a form of osteomalacia, can be induced in ovariectomized rats by long-term administration of cadmium (Cd). This IID rat model shows severe anemia, severe nephropathy, and osteomalacia accompanied by iron (Fe) deposition at the mineralization front. We characterized the pathogenesis of Cd-induced bone lesions by investigating the relationship between Fe deposition and osteoid tissue formation in ovariectomized rats. The rats were injected with CdCl
2 (0.5 mg/kg) for 70 weeks, with or without co-injection of erythropoietin (EPO) for varying lengths of time to elucidate whether EPO prevents and/or cures anemia, and, with the restoration from anemia, lessens the osteoid tissue formation. Necropsies were performed at 25, 50, or 70 weeks. Fe deposition at the mineralization front of bone was found at 50 weeks and increased thereafter. Animals injected with EPO showed decreased Fe deposition, although there was no relation between EPO administration and osteoid formation in the femur. Because the increase in bone lesion severity was independent of the amount of Fe deposition, we suggest that Fe deposition is not involved in the etiology of Cd-induced femoral bone lesions., (© 2020 John Wiley & Sons, Ltd.)- Published
- 2021
- Full Text
- View/download PDF
21. 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
22. Nasal hemangiopericytoma presenting with oncogenic osteomalasia: A case report and literature review.
- Author
-
Gökyer A, Sayın S, Küçükarda A, Çelik M, Güldiken S, and Çiçin İ
- Subjects
- Adult, Hemangiopericytoma genetics, Hemangiopericytoma surgery, Humans, Male, Mutation genetics, Nose Neoplasms genetics, Osteomalacia diagnostic imaging, Osteomalacia surgery, PHEX Phosphate Regulating Neutral Endopeptidase, Paraneoplastic Syndromes diagnostic imaging, Paraneoplastic Syndromes surgery, Hemangiopericytoma pathology, Nose Neoplasms pathology, Nose Neoplasms surgery, Osteomalacia pathology, Paraneoplastic Syndromes pathology
- Abstract
Sinonasal type hemangiopericytoma is a rare soft tissue tumor. Oncogenic osteomalacia (tumor-induced osteomalacia) is a rare syndrome that develops especially due to benign mesenchymal tumors. Nonspecific general bone pain and weakness delay the diagnosis and treatment of oncogenic osteomalacia, and it is difficult to determine the localization of the primary tumor causing oncogenic osteomalacia. A 43-year-old male patient with nasal hemangiopericytoma with symptoms of oncogenic osteomalacia is presented. The patient had musculoskeletal complaints at first and was diagnosed with lumbar disc herniation and surgery was performed. When his complaints recurred 1 year later, he was re-evaluated and diagnosed with hypophosphatemic osteomalacia. Despite the various treatments he received, his complaints did not decrease but increased, so a detailed examination was decided. When the positive PHEX mutation and very high fibroblast growth factor 23 level were detected, PET-CT imaging was performed with a pre-diagnosis of possible oncogenic osteomalacia, but no finding was found. Then he was evaluated with Ga-68 DOTATATE, and the soft tissue mass filling the right ethmoidal sinus was detected. Due to the relation of the mass with surrounding structures, it was considered unsuitable for total excision and incomplete surgical excision was performed. Pathologic evaluation revealed sinonasal type hemangiopericytoma (glomangiopericytoma). A significant remission in the patient's complaints was observed after the operation. Young patients with osteomalacia with unknown causes should be evaluated for malignancy, and screening and further examinations should be performed., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
- Full Text
- View/download PDF
23. 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
24. Nutritional Secondary Hyperparathyroidism and Fibrous Osteodystrophy in a Captive African Penguin ( Spheniscus demersus ) Similar to Osteomalacia in Poultry.
- Author
-
Palmieri C, Niemeyer C, Murray MJ, Ewbank AC, and Shivaprasad HL
- Subjects
- Animals, Animals, Zoo, Bird Diseases etiology, Bird Diseases pathology, Fatal Outcome, Female, Hyperparathyroidism, Secondary diagnosis, Hyperparathyroidism, Secondary etiology, Hyperparathyroidism, Secondary pathology, Osteomalacia diagnosis, Osteomalacia etiology, Osteomalacia pathology, Bird Diseases diagnosis, Hyperparathyroidism, Secondary veterinary, Osteomalacia veterinary, Spheniscidae
- Abstract
A 9-yr-old female black-footed African penguin ( Spheniscus demersus ) was presented for necropsy after a history of reproductive abnormalities, paresis of limbs, weakness, and sudden death. Postmortem examination revealed soft keel, collapsed rib cage with beading of the ribs, and bilateral parathyroid enlargement. Classic histologic lesions of fibrous osteodystrophy with osteomalacia were observed in the ribs, vertebrae, and to a lesser extent in the femur and tibiotarsus associated with hyperplasia of parathyroid glands. This represents the first report of nutritional secondary hyperparathyroidism in birds of the order Spheniciformes , most likely caused by low levels of calcium supplementation during egg laying. The reproductive abnormalities observed in this penguin and others from the same group (asynchronous egg-laying cycles, abnormal breeding behavior) were most likely exacerbated by the lack of an adequate photoperiod mimicking the natural daylight pattern.
- Published
- 2021
- Full Text
- View/download PDF
25. 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
26. A Challenging Case of Tumor-Induced Osteomalacia.
- Author
-
Paccou J, Pflimlin A, Glowacki F, and Cortet B
- Subjects
- Female, France, Humans, Magnetic Resonance Imaging methods, Middle Aged, Neoplasms pathology, Osteomalacia pathology, Radionuclide Imaging methods, Neoplasms complications, Osteomalacia etiology
- Published
- 2021
- Full Text
- View/download PDF
27. Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature.
- Author
-
Ni X, Li X, Zhang Q, Liu C, Gong Y, Wang O, Li M, Xing X, Jiang Y, and Xia W
- Subjects
- Adult, Bone Density, China, Humans, Hypophosphatemia, Osteomalacia pathology, Osteosclerosis pathology, Bone and Bones pathology, Familial Hypophosphatemic Rickets pathology
- Abstract
Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) was reported to be caused by homozygous mutation of dentin matrix protein 1 (DMP1). To date, very few cases have been reported. Here, we summarized clinical, laboratory and imaging findings of ARHR1 patients in our hospital. Literature review was performed to analyze genotype-phenotype correlation. Five Chinese patients from three unrelated pedigrees presented with lower extremity deformity and short stature. Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found. X-ray uncovered coexistence of osteomalacia and osteosclerosis. Although areal bone mineral density (aBMD) of axial bone measured by dual-energy X-ray absorptiometry was relatively high in all patients, volumetric BMD (vBMD) and microstructure of one adult patient's peripheral bone detected by HR-pQCT were damaged. Mutation analyses of DMP1 revealed three homozygous mutations including two novel mutations, c.54 + 1G > C and c.94C > A (p.E32X), and a reported mutation c.184-1G > A. Genotype-phenotype correlation analysis including 30 cases (25 from literature review and 5 from our study) revealed that patients harboring mutations affecting C-terminal fragment of DMP1 presented with shorter stature (Z score of height = - 3.4 ± 1.6 vs - 1.0 ± 1.6, p = 0.001) and lower serum phosphate level (0.70 ± 0.15 vs 0.84 ± 0.16, p = 0.03) than those harboring mutations only affecting N-terminal fragment. In summary, we reported five Chinese ARHR1 patients and identified two novel DMP1 mutations. High aBMD and local osteosclerosis in axial bone with low vBMD and damaged microstructure in peripheral bone were featured. Genotype-phenotype correlation analysis confirmed the important role of C-terminal fragment of DMP1.
- Published
- 2020
- Full Text
- View/download PDF
28. Mineralized tissues in hypophosphatemic rickets.
- Author
-
Robinson ME, AlQuorain H, Murshed M, and Rauch F
- Subjects
- Absorptiometry, Photon, Bone Development drug effects, Bone Development genetics, Bone and Bones diagnostic imaging, Bone and Bones pathology, Calcification, Physiologic drug effects, Calcification, Physiologic genetics, Calcitriol administration & dosage, Familial Hypophosphatemic Rickets diagnosis, Familial Hypophosphatemic Rickets drug therapy, Familial Hypophosphatemic Rickets genetics, Fibroblast Growth Factor-23, Fibroblast Growth Factors antagonists & inhibitors, Humans, Osteocytes metabolism, Osteomalacia diagnosis, Osteomalacia drug therapy, Osteomalacia genetics, PHEX Phosphate Regulating Neutral Endopeptidase metabolism, Paracrine Communication genetics, Phosphates administration & dosage, Phosphates blood, Renal Reabsorption drug effects, Renal Reabsorption genetics, Tooth growth & development, Tooth pathology, Treatment Outcome, Familial Hypophosphatemic Rickets pathology, Fibroblast Growth Factors metabolism, Osteomalacia pathology, PHEX Phosphate Regulating Neutral Endopeptidase genetics, Phosphates metabolism
- Abstract
Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.
- Published
- 2020
- Full Text
- View/download PDF
29. Osteoporosis, osteomalacia, and hip fracture: A case study from the Terry collection.
- Author
-
Morgan B, Mant M, de la Cova C, and Brickley MB
- Subjects
- Aged, Female, Humans, Paleopathology, Pelvic Bones pathology, Vitamin D Deficiency pathology, Hip Fractures pathology, Osteomalacia pathology, Osteoporosis pathology
- Abstract
Objective: This case study describes a perimortem hip fracture in a documented individual from the Robert J. Terry Skeletal Collection. The purpose of this paper is to comprehend how co-occurring conditions contributed to fracture risk and to understand the effect of the injury on this individual., Materials and Methods: A 73-year-old female from the Terry Collection with a fracture of the left proximal femur was assessed macroscopically, and images were taken with a Keyence VHX-2000 digital microscope. Documentation concerning the individual's history and contemporary treatment of hip fractures was explored., Results: Assessment demonstrated impaction of fractured elements occurred as a result of the inferior displacement of the femoral head into the femoral neck. Eburnation and hinge fractures are present on the fracture margins. Bending deformities of the sacrum, sternum, and ribs indicate underlying osteomalacia. No evidence of surgical intervention was observed., Conclusions: Both osteomalacia and osteoporosis contributed to overall fracture risk in this case, which demonstrates how complex underlying factors can interact to increase the probability of fracture, and influence post-fracture mortality., Significance: This report is the first case study, to date, of a healing hip fracture in which the circumstances of the fracture and the medical history of the individual are known., Limitations: To fully investigate osteoporosis, bone mineral density for this individual should be compared with others in the collection., Suggestions for Further Research: The effect of co-occurring conditions on fracture risk should be explored in the wider Terry Collection, and in other skeletal collections., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
30. 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
31. 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
32. 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
33. Perimortem fracture manifestations and mortality after hip fracture in a documented skeletal series.
- Author
-
Mant M, de la Cova C, Ives R, and Brickley MB
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Osteomalacia pathology, Radiography methods, Fractures, Bone pathology, Hip Fractures pathology, Pelvic Bones pathology, Wounds and Injuries pathology
- Abstract
Objective: Unhealed hip fractures are underrepresented in the archaeological record, suggesting that better identification criteria are required. This paper evaluates whether a sample of documented perimortem hip fractures displayed classic perimortem features and which features may facilitate better identification of such fractures in the archaeological record., Materials: Ten individuals from the Robert J. Terry Anatomical Skeletal Collection with documented hip fractures and intervals of survival., Methods: We observed the skeletal remains macroscopically and with a Keyence VHX-2000 digital microscope at a range of 5x to 100x magnification., Results: 90% of the individuals and 64% of the fragments had identifiable perimortem features; hinging was the most consistent feature. Eburnation was found in two individuals who died 13 days after sustaining a hip fracture., Conclusions: This study underscores the importance of examining fracture margins for evidence of hinging. Eburnation may be added to the list of potential perimortem fracture identification criteria., Significance: Identifying perimortem trauma unequivocally remains challenging. Using collections with documented perimortem fractures aids in determining which criteria are most likely to appear in archaeological human bone., Limitations: The fracture location patterning (70% intertrochanteric) may be the result of sample selection., Suggestions for Future Research: Further intensive comparative investigation with the Hamann-Todd Collection would elucidate patterns further., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
34. Elevated FGF23 in a patient with hypophosphatemic osteomalacia associated with neurofibromatosis type 1.
- Author
-
Sahoo SK, Kushwaha P, Bharti N, Khedgikar V, Trivedi R, Agrawal V, Ahmad N, Zaidi G, Pal L, Ito N, and Bhatia E
- Subjects
- Adult, Female, Fibroblast Growth Factor-23, Humans, Hypophosphatemia diagnostic imaging, Hypophosphatemia pathology, Neurofibromatosis 1 diagnostic imaging, Neurofibromatosis 1 pathology, Osteomalacia diagnostic imaging, Osteomalacia pathology, Fibroblast Growth Factors metabolism, Hypophosphatemia complications, Hypophosphatemia metabolism, Neurofibromatosis 1 complications, Neurofibromatosis 1 metabolism, Osteomalacia complications, Osteomalacia metabolism
- Abstract
Context: The mechanism behind hypophosphatemia in the setting of neurofibromatosis type 1 (NF1) is not known. We describe a possible role of fibroblast growth factor-23 (FGF23) in the pathophysiology of hypophosphatemia in a patient with NF1., Case Description: A 34-year woman with NF1 presented with severe hypophosphatemia, osteomalacia, and elevated plasma FGF23. The patient had considerable improvement on replacement of oral phosphate. Two Ga68 DOTANOC PET-CT scans over a period of 2 years failed to detect any localized uptake. Immuno-staining for FGF23 was absent in the neural-derived tumour cells of the neurofibromas in the proband., Conclusion: The patient with NF1 had elevated circulating FGF23. Tumour cells in the neurofibroma tissues did not stain for FGF23 on IHC. It is unlikely for neurofibromas to contribute to high circulating FGF23 levels in the proband., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
35. Phosphaturic Mesenchymal Tumor of Soft Tissue of the Foot: Report of a Case With Review of the Literature.
- Author
-
Bisceglia M, Galliani CA, Fraternali Orcioni G, Perrone E, Del Giudice A, and Scillitani A
- Subjects
- Adult, Bone and Bones metabolism, Fibroblast Growth Factor-23, Humans, Male, Mesenchymoma diagnosis, Osteomalacia diagnosis, Soft Tissue Neoplasms diagnosis, Fibroblast Growth Factors blood, Mesenchymoma pathology, Osteomalacia pathology, Phosphates metabolism, Soft Tissue Neoplasms pathology
- Abstract
Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that ectopically secretes fibroblast growth factor 23, a bone cell-derived protein that regulates phosphate homeostasis. The overproduction of fibroblast growth factor 23 causes a paraneoplastic syndrome characterized by hyperphosphaturia, hypophosphatemia, hypovitaminosis D, and vitamin D refractory rickets/osteomalacia, effects that disappear with tumor removal. The PMT may occur in several anatomic regions, mainly in the limbs, usually involving both soft tissue and bone. Acral locations occur in 10% to 15% of the cases, mostly in the feet, with 95 cases reported in this anatomic region to date. We report a case of a PMT in a young adult male who presented in 2007 with the classic constellation of signs and symptoms. A small soft-tissue tumor was detected in his right heel, 3 years after exhaustively seeking for it by various imaging techniques performed at different institutions. Before the tumor was detected, attempts to manage this patient's osteomalacia with phosphate and vitamin D (both calcitriol and ergocalciferol) supplementation were unsuccessful. Following surgical resection, the patient experienced prompt correction of the phosphaturia and gradual reconstitution of his bone mineralization. The pathologic diagnosis was (benign) PMT, mixed connective tissue type. In 2019, 12 years after resection, the patient is asymptomatic, and his bone mineral homeostasis has been restored.
- Published
- 2019
- Full Text
- View/download PDF
36. The synergy between radiographic and macroscopic observation of skeletal lesions on dry bone.
- Author
-
Biehler-Gomez L, Tritella S, Martino F, Campobasso CP, Franchi A, Spairani R, Sardanelli F, and Cattaneo C
- Subjects
- Aged, Aged, 80 and over, Arthritis, Rheumatoid pathology, Body Remains diagnostic imaging, Body Remains pathology, Diabetes Mellitus pathology, Female, Forensic Anthropology, Humans, Male, Middle Aged, Multiple Myeloma pathology, Neoplasm Metastasis pathology, Osteomalacia pathology, Bone and Bones diagnostic imaging, Bone and Bones pathology, Radiography
- Abstract
The diagnosis of bone lesions is a fundamental part of the study of skeletal remains, both in the archeological and forensic context. On the one side, the literature proved the relevance of radiography for the detection of bone lesions; on the other side, the careful macroscopic observation of the morphology of bone lesions is often underestimated. For this study, we examined and performed plain radiography on 14 skeletons of the CAL Milano Cemetery Skeletal Collection diagnosed with rheumatoid arthritis, diabetes, multiple myeloma, metastatic cancer, and osteomalacia to compare the macroscopic morphology and radiographic visualization of bone lesions. At least 200 osteolytic lesions and 65 areas of proliferative bone reaction (either spongiosclerotic or periosteal) were studied. We realized "comparative sets" of macroscopic pictures and radiographic imaging of the same skeletal elements to allow comparisons of detection and recognition of bone lesions. As a result, while trabecular lesions may be lost through naked eye observation, many lesions can also be unperceived on radiographs due to contrast, including periosteal reactions, osteolytic lesions, and spongiosclerosis. The aim of this research was to investigate the strengths and pitfalls of digital radiography and macroscopic analysis and to demonstrate the synergy of a complementary approach between the two methods for lesion analysis in dry bone.
- Published
- 2019
- Full Text
- View/download PDF
37. 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
38. Analysis of patterning in the occurrence of skeletal lesions used as indicators of vitamin D deficiency in subadult and adult skeletal remains.
- Author
-
Brickley MB, Mays S, George M, and Prowse TL
- Subjects
- Adolescent, Child, Child, Preschool, Female, History, Ancient, History, Medieval, Humans, Infant, Infant, Newborn, Male, Osteomalacia diagnosis, Osteomalacia pathology, Rickets diagnosis, Rickets pathology, Vitamin D Deficiency diagnosis, Vitamin D Deficiency pathology, Young Adult, Osteomalacia history, Paleopathology methods, Rickets history, Vitamin D Deficiency history
- Abstract
Paleopathological investigations of conditions linked to vitamin D deficiency have increased in the last twenty years, and a suite of skeletal lesions has been established to aid in the diagnosis of vitamin D deficiency disease in subadults and adults. This paper analyzes the occurrence of these lesions in a large skeletal series comprising 3541 Roman period individuals (1st-6th century AD). Sixteen lesions reported in rickets in subadults, and 13 associated with residual rickets and osteomalacia in adults, were analyzed. Among subadults, there were clear associations among post-cranial lesions. Porotic cranial changes were associated with each other, but not with post-cranial lesions. A range of conditions could have produced the cranial lesions. There was a general paucity of correlations between indicators found in adults, and the difficulty in recording bending deformities was clear. Pseudofractures appear to provide a useful means of investigating osteomalacia in adults. In general, a simple algorithmic approach using presence or absence of lesions is unlikely to provide an adequate means of diagnosing vitamin D deficiency in paleopathology. Knowledge and consideration of the underlying physiological mechanisms involved in lesion formation, combined with individual judgement, will be required to differentially diagnose cases., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
39. Radiographically recognizable? An investigation into the appearance of osteomalacic pseudofractures.
- Author
-
Jennings E, Buckberry J, and Brickley MB
- Subjects
- Adult, History, 15th Century, History, 18th Century, History, 19th Century, History, Medieval, Humans, Osteomalacia diagnostic imaging, Osteomalacia history, Osteomalacia pathology
- Abstract
Pseudofractures, lucent bands that occur due to a build-up of osteoid, are a key feature of osteomalacia. In paleopathology, pseudofractures are often marked by small, linear cracks in the cortex of the bone surrounded by irregular, bony spicule formation. Radiography can be used to help diagnose pseudofractures, both clinically and in paleopathology. A detailed understanding of the radiographic appearance of pseudofractures and their development is, therefore, necessary to aid a diagnosis of vitamin D deficiency. The present study examined the clinical literature to determine current ideas on the appearance of pseudofractures with the aim of applying this knowledge to paleopathology. A radiographic study of the characteristics of pseudofractures was performed on five individuals with clear skeletal features of osteomalacia from archaeological sites in Canada and the United Kingdom dating to the medieval period (5th to 15th centuries) and the 18th to 19th century. Results show that the radiographic appearance of pseudofractures could potentially reveal information about the cause of the deficiency and the chronicity of pseudofractures. This type of information has the potential to further our understanding of the lived experiences of archaeological individuals with osteomalacia., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
40. Four possible cases of osteomalacia: The value of a multidisciplinary diagnostic approach.
- Author
-
van der Merwe AE, Veselka B, van Veen HA, van Rijn RR, Colman KL, and de Boer HH
- Subjects
- Adult, Female, Humans, Middle Aged, History, 19th Century, History, 20th Century, Netherlands, Osteomalacia diagnostic imaging, Osteomalacia history, Osteomalacia pathology
- Abstract
Rickets and residual rickets are often encountered in Dutch archeological skeletal samples. However, no archeological Dutch paleopathological case of adult osteomalacia has been described in literature to date. This paper describes the first four archeological Dutch paleopathological cases of osteomalacia and assesses the value of the various modalities (macroscopic assessment, radiology and histology) that may be used for diagnosis. The skeletal remains investigated originate from the Meerenberg psychiatric hospital cemetery in Bloemendaal, the Netherlands, and date from 1891 - 1936. The remains of 69 adult individuals were inspected for macroscopic lesions which may be associated with osteomalacia. In cases suspect for osteomalacia, complimentary radiological and histological investigations (BSE-SEM and light microscopy) were performed. Macroscopically, four individuals presented with lesions (highly) suggestive of osteomalacia. Histological examination (both BSE-SEM and light microscopy) provided valuable information to come to an eventual diagnosis of osteomalacia in all four cases. Light microscopy proved to be an feasible alternative for BSE-SEM. The added value of radiological analyses was limited. The individuals identified were most likely patients in the psychiatric hospital, and the reason for their institutionalization and/or the regime in the institution may have played a role in the development of the osteomalacia observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
41. Contribution of ultrasound to diagnosing a phosphaturic mesenchymal tumor.
- Author
-
Busquet F, Gahier-Penhoat M, Lescour V, Maugars Y, and Guillot P
- Subjects
- Diagnosis, Differential, Humans, Hypophosphatemia, Familial diagnosis, Male, Mesenchymoma pathology, Middle Aged, Osteomalacia pathology, Risk Assessment, Soft Tissue Neoplasms pathology, Thigh, Hypophosphatemia, Familial complications, Mesenchymoma diagnostic imaging, Osteomalacia diagnostic imaging, Soft Tissue Neoplasms diagnostic imaging, Ultrasonography, Doppler methods
- Published
- 2018
- Full Text
- View/download PDF
42. Soluble Klotho causes hypomineralization in Klotho-deficient mice.
- Author
-
Minamizaki T, Konishi Y, Sakurai K, Yoshioka H, Aubin JE, Kozai K, and Yoshiko Y
- Subjects
- Animals, Animals, Newborn, Bone and Bones drug effects, Bone and Bones physiology, Cells, Cultured, Female, Fibroblast Growth Factor-23, Fibroblast Growth Factors metabolism, Klotho Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoblasts drug effects, Osteoblasts physiology, Osteocytes drug effects, Osteocytes physiology, Osteomalacia blood, Osteomalacia chemically induced, Osteomalacia pathology, PHEX Phosphate Regulating Neutral Endopeptidase drug effects, PHEX Phosphate Regulating Neutral Endopeptidase metabolism, Pregnancy, Protein Isoforms pharmacology, Rats, Rats, Wistar, Rickets blood, Rickets chemically induced, Rickets pathology, Signal Transduction drug effects, Signal Transduction genetics, Solubility, Calcification, Physiologic drug effects, Glucuronidase genetics, Glucuronidase pharmacology, Osteomalacia genetics, Rickets genetics
- Abstract
The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient ( kl/kl ) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro , in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone., (© 2018 Society for Endocrinology.)
- Published
- 2018
- Full Text
- View/download PDF
43. [Rickets/Osteomalacia. FGF23-related hypophosphatemic rickets/osteomalacia.]
- Author
-
Fukumoto S
- Subjects
- Fibroblast Growth Factor-23, Humans, Familial Hypophosphatemic Rickets pathology, Fibroblast Growth Factors, Osteomalacia pathology, Rickets, Hypophosphatemic pathology
- Abstract
FGF23 is a hormone that reduces blood phosphate level. Excessive actions of FGF23 result in several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets and tumor-induced osteomalacia. It is not clear how excessive actions of FGF23 are induced in these diseases. The inhibition of excessive FGF23 actions is a promising new treatment for FGF23-related hypophosphatemic rickets/osteomalacia.
- Published
- 2018
- Full Text
- View/download PDF
44. 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
45. 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
46. Tumour-induced osteomalacia.
- Author
-
Minisola S, Peacock M, Fukumoto S, Cipriani C, Pepe J, Tella SH, and Collins MT
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Bone and Bones metabolism, Bone and Bones pathology, Female, Fibroblast Growth Factor-23, Fibroblast Growth Factors genetics, Fibronectins metabolism, Fractures, Bone diagnosis, Fractures, Bone etiology, Humans, Hypophosphatemia blood, Japan epidemiology, Male, Middle Aged, Muscle Weakness diagnosis, Muscle Weakness etiology, Neoplasms, Connective Tissue metabolism, Neoplasms, Connective Tissue physiopathology, Neoplasms, Connective Tissue surgery, Osteomalacia epidemiology, Osteomalacia metabolism, Pain diagnosis, Pain etiology, Paraneoplastic Syndromes diagnosis, Paraneoplastic Syndromes etiology, Phosphates therapeutic use, Protein Processing, Post-Translational genetics, Receptor, Fibroblast Growth Factor, Type 1, Vitamin D metabolism, Vitamin D therapeutic use, Fibroblast Growth Factors metabolism, Hypophosphatemia complications, Neoplasms, Connective Tissue diagnosis, Osteomalacia pathology, Phosphates blood
- Abstract
Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.
- Published
- 2017
- Full Text
- View/download PDF
47. The Spectrum of Vitamin D Deficiency: Description of a Family.
- Author
-
Vierucci F, Del Pistoia M, Randazzo E, Massart F, and Federico G
- Subjects
- Adolescent, Adult, Age Factors, Child, Family, Female, Humans, Infant, Male, Risk Factors, Osteomalacia blood, Osteomalacia pathology
- Abstract
Background Vitamin D deficiency represents a global health problem, affecting children and adolescents worldwide. Objects To confirm that vitamin D deficiency can present as a spectrum of clinical pictures. Methods We diagnosed nutritional rickets in a 10-month-old infant of Senegal origin with several risk factors for vitamin D deficiency. As many of these factors affected also his cohabitant relatives, we evaluate infant's family members (mother and 4 brothers) looking for other vitamin D deficiency-related comorbidities. Results 3 brothers had asymptomatic vitamin D deficiency and 2 of them (9.8 and 13.4 years-old) showed secondary hyperparathyroidism. The fourth brother (11.3 years-old) had nutritional rickets. Their mother was affected by osteomalacia. None of them received vitamin D supplementation. Conclusion Vitamin D deficiency may present as a spectrum of clinical pictures, representing a continuum ranging from asymptomatic/subtle conditions to overt rickets/osteomalacia. Immigrant families are at high risk for vitamin D deficiency at every age. If a case of symptomatic vitamin D deficiency is recognized, then the evaluation of the all family members is recommended, as they can have the same and/or other risk factors for vitamin D deficiency., Competing Interests: Conflicts of Interest: The authors have no conflict of interest to disclose., (© Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2017
- Full Text
- View/download PDF
48. 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
49. Showcasing the breadth of endocrinology.
- Subjects
- Adipose Tissue pathology, Awards and Prizes, Female, Humans, Menopause, Microscopy, Confocal, Osteomalacia pathology, Ovary pathology, Pituitary Gland pathology, Diabetes Mellitus, Type 2 pathology, Endocrinology, Intra-Abdominal Fat pathology, Pancreas pathology, Periodicals as Topic
- Published
- 2016
- Full Text
- View/download PDF
50. The Return of Congenital Rickets, Are We Missing Occult Cases?
- Author
-
Elidrissy AT
- Subjects
- Animals, Celiac Disease congenital, Celiac Disease etiology, Humans, Hypocalcemia pathology, Osteomalacia pathology, Breast Feeding, Osteomalacia etiology, Rickets congenital, Rickets epidemiology, Vitamin D Deficiency complications
- Abstract
Congenital rickets is the term given to fetus born with clinical features of rickets, but those born with biochemical evidence of rickets without obvious clinical features still can be considered occult congenital rickets. Some of the affected babies with this disease have the intrauterine rachitic environment, but a calcium trans-placental pump prevents the fetus from having clinical features of rickets. They may present with hypocalcemia few days after birth or later with more florid features of rickets. Congenital rickets cases born with florid features reported over the last 40 years are few and can be divided into two groups. The first due to severe maternal osteomalacia in which their bones were so decalcified to have enough calcium to be pumped to their fetus. Another group in which newborn babies were hypocalcemic due to other maternal diseases as malabsorption, celiac disease, pre-eclampsia, and prematurity. All inherited rickets cases per se, or as part of other syndromes can be considered congenital rickets. Most cases seen in our region are due to maternal vitamin D deficiency with symptoms becoming obvious when the infants are breastfed, or may present with hypocalcemic convulsions or craniotabes. This is a review of congenital rickets with the aim of shedding light on this potentially acute disease that needs more attention and awareness in the neonatal period to avoid rare serious complications as cardiomyopathy or myelofibrosis and the complications of hypocalcemic convulsions. Congenital rickets cases seen simulate a tip of an ice-burg and its prevention is an important issue, especially with the tremendous urbanization with tall buildings living in sun-deprived flats as the commonest type of residence leading to the increasing incidence of maternal osteomalacia and rickets.
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.