RESUMO
Bone deformities and fractures are common consequences of renal osteodystrophy in the dialysis population. Persistent hypophosphatemia may be observed with more frequent home hemodialysis regimens, but the specific effects on the skeleton are unknown. We present a patient with end-stage renal disease treated with frequent home hemodialysis who developed severe bone pain and multiple fractures, including a hip fracture and a tibia-fibula fracture complicated by nonunion, rendering her nonambulatory and wheelchair bound for more than a year. A bone biopsy revealed severe osteomalacia, likely secondary to chronic hypophosphatemia and hypocalcemia. Treatment changes included the addition of phosphate to the dialysate, a higher dialysate calcium concentration, and increased calcitriol dose. Several months later, the patient no longer required a wheelchair and was able to ambulate without pain. Repeat bone biopsy revealed marked improvements in bone mineralization and turnover parameters. Also, with increased dialysate phosphate and calcium concentrations, as well as increased calcitriol, circulating fibroblast growth factor 23 levels increased.
Assuntos
Fraturas Ósseas , Hemodiálise no Domicílio/efeitos adversos , Hipofosfatemia/diagnóstico , Falência Renal Crônica/terapia , Osteomalacia , Fosfatos , Calcificação Fisiológica/efeitos dos fármacos , Calcificação Fisiológica/fisiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/diagnóstico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Soluções para Diálise/farmacologia , Gerenciamento Clínico , Feminino , Fator de Crescimento de Fibroblastos 23 , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/etiologia , Fraturas Ósseas/terapia , Hemodiálise no Domicílio/métodos , Humanos , Testes de Função Renal/métodos , Efeitos Adversos de Longa Duração/sangue , Efeitos Adversos de Longa Duração/diagnóstico , Pessoa de Meia-Idade , Osteomalacia/sangue , Osteomalacia/diagnóstico , Osteomalacia/etiologia , Fosfatos/administração & dosagem , Fosfatos/metabolismo , Resultado do TratamentoRESUMO
Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.
Assuntos
Neoplasias de Tecido Conjuntivo/diagnóstico , Pequim , Biomarcadores/sangue , Estudos de Coortes , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Hospitais de Ensino , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/etiologia , Hipofosfatemia/fisiopatologia , Deslocamento do Disco Intervertebral/sangue , Deslocamento do Disco Intervertebral/diagnóstico , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/fisiopatologia , Masculino , Prontuários Médicos , Neoplasias de Tecido Conjuntivo/sangue , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/fisiopatologia , Osteomalacia/sangue , Osteomalacia/diagnóstico , Osteomalacia/diagnóstico por imagem , Osteomalacia/fisiopatologia , Osteoporose/sangue , Osteoporose/diagnóstico , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Síndromes Paraneoplásicas , Estudos Retrospectivos , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/fisiopatologiaRESUMO
BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. Nonspecific symptoms make the diagnosis elusive. In addition, locating the responsible tumor(s) is challenging. The aim of this study was to investigate the clinical management and outcomes of TIO. METHODS: The clinical features, diagnostic procedures, treatment, and outcomes of 12 patients were reviewed retrospectively. RESULTS: The cohort comprised six men and six women (mean age 45.5 ± 9.9 years, range 23-61 years). The mean duration of disease was 3.7 ± 2.6 years. All patients manifested progressive bone pain, muscle weakness, and/or difficulty walking. Serum phosphorus concentrations were low in all patients (mean 0.42 ± 0.12 mmol/L). Technetium-99m octreotide scintigraphy was performed in 11 patients and showed lesions in the right distal femur, left femoral head, and right tibial plateau, respectively, in three patients. Magnetic resonance imaging (MRI) was negative for lesions in one patient. Two patients underwent biopsies that showed negative histopathology. Two patients, at 2 years and 8 months, respectively, after having negative technetium-99m octreotide studies, underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT), which revealed lesions in the sacrum and soft tissue of the left palm, respectively. One tumor was detected by CT and MRI. Overall, lesion sites were the head (two patients, 16.7%), thoracic and lumbar region (two, 16.7%), pelvis (three, 25%), lower limbs (four, 33.3%), and upper limbs (one, 8.3%). All patients underwent surgery, and histopathology showed phosphaturic mesenchymal tumors in each. Postoperatively, serum phosphorus concentrations normalized within 2-7 days in 11 patients. With follow-ups of 1-41 months, surgery was effective in 10 patients. One patient developed local recurrence and another had metastases. CONCLUSIONS: Locating tumors responsible for tumor-induced osteomalacia is often challenging. Although complete tumor resection confers a good prognosis in most patients, surveillance for recurrence and metastasis is necessary. Before surgery or when surgery is not indicated, oral phosphate can alleviate symptoms and metabolic imbalance.
Assuntos
Hipofosfatemia/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Síndromes Paraneoplásicas/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/sangue , Neoplasias de Tecido Conjuntivo/cirurgia , Osteomalacia/sangue , Osteomalacia/diagnóstico por imagem , Osteomalacia/cirurgia , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/cirurgia , Fosfatos/sangue , Estudos Retrospectivos , Neoplasias de Tecidos Moles/sangue , Neoplasias de Tecidos Moles/cirurgia , Resultado do TratamentoRESUMO
PURPOSE: Fibroblast growth factor 23 (FGF23) is a hormone regulating phosphate metabolism. Excessive actions of FGF23 cause several types of FGF23-related hypophosphatemic rickets/osteomalacia. Recently, it was reported that FGF23 levels were independently correlated with left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). In addition, FGF23 was also shown to cause cardiac hypertrophy directly acting on cardiomyocytes. However, there is no study indicating the correlation between FGF23 and LVH in adult patients with FGF23-related hypophosphatemic rickets/osteomalacia. Therefore, we examined the existence of LVH in these patients. MATERIALS AND METHODS: We recruited consecutive 24 patients with FGF23-related hypophosphatemic diseases. Their serum intact FGF23 levels and the parameters associated with LVH, including left ventricular mass index (LVMI), relative wall thickness (RWT), Sokolow-Lyon voltage, and Cornell product, were measured. The correlations between FGF23 and these parameters were examined. RESULTS: The participants did not show LVH on the whole. In addition, no significant correlation was observed by these examinations. CONCLUSION: It seems unlikely that FGF23 levels are the apparent determinant of the cardiac mass in patients with FGF23-related hypophosphatemic rickets/osteomalacia.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Hipertrofia Ventricular Esquerda/sangue , Osteomalacia/sangue , Raquitismo Hipofosfatêmico/sangue , Adulto , Idoso , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , GTP Fosfo-Hidrolases/genética , Hipofosfatemia/genética , Proteínas de Membrana/genética , Nevo Pigmentado/genética , Osteomalacia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/genética , Adolescente , Criança , Exoma , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/patologia , Masculino , Mutação , Nevo , Nevo Pigmentado/sangue , Nevo Pigmentado/patologia , Osteomalacia/sangue , Osteomalacia/patologia , Análise de Sequência de DNA , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologiaRESUMO
Human body acquires a significant amount of vitamin D by cutaneous synthesis under the action of sunlight and less is supplied through nutritional sources. Diversified sociocultural and economic determinants have been identified that limit the dietary intake of vitamin D and enough distribution of sunlight to maintain optimal levels of 25-hydroxyvitamin D (25(OH)D). Consequently, the world has witnessed a high prevalence of hypovitaminosis D in resource-limited South Asian countries. The purpose of this review is to provide a South Asian perspective of vitamin D status, critically examining India, Pakistan, Bangladesh, and Sri Lanka, and to shed light on potential determinants (latitude and season, sunshine exposure habits, age, gender, and genetic factors) leading to hypovitaminosis D among a variety of population groups. Literature search was carried out using bibliographic databases "PubMed," "Google Scholar," and "ScienceDirect.com." Serum 25(OH)D level, 20-50 nmol/L, was mainly taken as vitamin D deficiency, and determinants of low serum 25(OH)D concentration of the population under study were also considered. The review concludes that vitamin D deficiency is highly prevalent among South Asian populations and global efforts are needed to overcome hypovitaminosis in the region. In addition, dietary diversification, supplementation and fortification of foods with vitamin D, adequate exposure to sunlight, and consumption of animal foods were suggested as viable approaches to maintain 25(OH)D levels for optimal health.
Assuntos
Alimentos Fortificados , Estado Nutricional , Osteomalacia/epidemiologia , Raquitismo/epidemiologia , Deficiência de Vitamina D/epidemiologia , Vitamina D/sangue , Povo Asiático , Bangladesh , Dieta , Suplementos Nutricionais , Humanos , Índia , Osteomalacia/sangue , Paquistão , Prevalência , Raquitismo/sangue , Estações do Ano , Sri Lanka , Luz Solar , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangueAssuntos
Anemia Ferropriva/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Compostos Férricos/efeitos adversos , Fatores de Crescimento de Fibroblastos/sangue , Hipofosfatemia/tratamento farmacológico , Maltose/análogos & derivados , Osteomalacia/tratamento farmacológico , Adulto , Anemia Ferropriva/sangue , Compostos Férricos/uso terapêutico , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/induzido quimicamente , Masculino , Maltose/efeitos adversos , Maltose/uso terapêutico , Osteomalacia/sangue , Osteomalacia/induzido quimicamente , Resultado do TratamentoRESUMO
Tumor-induced osteomalacia (TIO) has long been recognized as a clinical paraneoplastic syndrome. The identification of a unique histopathologic entity, the phosphaturic mesenchymal tumor (PMT), as a distinct etiology for TIO has been a more recent discovery. The majority of published cases describe a solitary, non-aggressive appearing soft tissue or osseous lesions in patients with osteomalacia; aggressive appearing or multifocal lesions appear to be exceedingly rare. These tumors characteristically secrete fibroblast growth factor 23 (FGF23). Elevated serum levels of FGF23 result in phosphate wasting and osteomalacia. In the majority of cases, laboratory abnormalities and clinical signs and symptoms of osteomalacia precede identification of the causative lesion by years. Following diagnosis, complete resection with wide margins to prevent local recurrence is most often curative. Imaging characteristics of PMT are diverse and remain incompletely defined, as the majority of previous publications are outside of the radiologic literature. We present multiple imaging modalities in two cases of patients with debilitating osteomalacia and unusual appearing PMTs: one with a locally aggressive lesion leading to pathologic fracture, the second presenting with exceedingly rare multifocal PMT.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Osteomalacia/diagnóstico , Osteomalacia/etiologia , Síndromes Paraneoplásicas/sangue , Neoplasias de Tecidos Moles/sangue , Neoplasias de Tecidos Moles/patologia , Biomarcadores Tumorais/sangue , Diagnóstico Diferencial , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Osteomalacia/sangue , Síndromes Paraneoplásicas/diagnóstico , Fósforo/sangueRESUMO
The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.
Assuntos
Proteínas da Matriz Extracelular/genética , Minerais/metabolismo , Osteócitos/fisiologia , Osteomalacia/genética , Fosfoproteínas/genética , Raquitismo/genética , Adulto , Animais , Osso e Ossos/patologia , Calcificação Fisiológica/genética , Calcificação Fisiológica/fisiologia , Células Cultivadas , Análise Mutacional de DNA , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteócitos/patologia , Osteomalacia/sangue , Osteomalacia/patologia , Fosfatos/metabolismo , Raquitismo/sangue , Raquitismo/patologiaRESUMO
PURPOSE OF REVIEW: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a complex disorder of bone and mineral metabolism that results in an excess risk of fractures, cardiovascular events and mortality. The management of the bone disorder aspect of CKD-MBD may require bone biopsy to determine appropriate treatment strategies. However, it is unclear when biopsy may be necessary and whether or not state-of-the art imaging and serologic testing can supplant the bone biopsy as a tool to assist with management decisions. RECENT FINDINGS: Advances in imaging methods now permit the noninvasive assessment of structural aspects of bone quality. Furthermore, common bone imaging tools, such as dual-energy X-ray absorptiometry, can be used to stratify for fracture risk. Circulating markers of bone turnover can be used to assess the risk of bone loss and fracture, but they are less useful in diagnosing the type of renal osteodystrophy. SUMMARY: Although advances in imaging now permit the assessment of fracture risk more accurately in CKD patients, the assessment of the type of renal osteodystrophy remains poor without bone biopsy. The virtual bone biopsy will be possible only when we are able to noninvasively assess turnover with good accuracy. A bone biopsy is needed when the bone turnover is unclear.
Assuntos
Biópsia , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Osteomalacia/sangue , Insuficiência Renal Crônica/complicações , Absorciometria de Fóton , Densidade Óssea , Remodelação Óssea/fisiologia , Osso e Ossos/fisiopatologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/diagnóstico por imagem , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Fraturas Ósseas/epidemiologia , Humanos , Minerais/metabolismo , Tomografia Computadorizada por Raios XRESUMO
Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.
Assuntos
Proteínas ADAM/metabolismo , Matriz Óssea/metabolismo , Colágeno Tipo I/metabolismo , Osteomalacia/metabolismo , Proteólise , Raquitismo/metabolismo , Proteína ADAMTS1 , Animais , Densidade Óssea , Calcificação Fisiológica , Colágeno Tipo I/sangue , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Humanos , Camundongos , Camundongos Transgênicos , Osteoblastos/metabolismo , Osteomalacia/sangue , Raquitismo/sangueRESUMO
Some of the hypophosphatemic rickets/osteomalacia are caused by the increased bioactivity of FGF23, and classified into FGF23-mediated hypophosphatemic rickets/osteomalacia. This group includes various disorders such as X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia, tumor-induced osteomalacia, and rickets/osteomalacia caused by the administration of iron polymaltose or saccharated ferric oxide. Measurement of serum levels of FGF23 is useful for diagnosis of these conditions. In the adult patients with FGF23-mediated hypophosphatemic rickets/osteomalacia, mineralizing enthesoopathy is an often observed complication.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Osteomalacia/diagnóstico , Raquitismo Hipofosfatêmico/diagnóstico , Diagnóstico Diferencial , Compostos Férricos/efeitos adversos , Óxido de Ferro Sacarado , Fator de Crescimento de Fibroblastos 23 , Ácido Glucárico/efeitos adversos , Humanos , Osteomalacia/sangue , Osteomalacia/etiologia , Fosfatos/sangue , Raquitismo Hipofosfatêmico/sangue , Raquitismo Hipofosfatêmico/etiologiaRESUMO
A 93 year-old woman with Paget's disease of bone had been treated with etidronate without interruption during 20 years. The daily dose was usual (5mg/kg/day) but this prescription had never been stopped by her physicians. Two fractures had already occurred in pagetic (right tibia) and non pagetic bones (right fibula) within the last 2 years, and she presented rib fractures, another right tibia fracture and right femur fracture during hospitalization time. X-rays films showed major osteolysis of left ulna and right tibia. Blood samples and technetium bone scan brought no evidence for sarcoma or lytic evolution of the disease. A transiliac bone biopsy on non pagetic bone site confirmed the diagnosis of osteomalacia (increased osteoid parameters), with secondary hyperparathyroidism (hook resorption). In Paget's disease of bone, continuous treatment by etidronate may induce generalized osteomalacia, and increase the risk of fracture in both pagetic and non-pagetic bones. Whereas physicians and pharmaceutical industry try to improve the observance of those drugs, this striking observation also points out that a prescription always needs to be updated.
Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Ácido Etidrônico/efeitos adversos , Fraturas Espontâneas/etiologia , Osteíte Deformante/tratamento farmacológico , Osteomalacia/induzido quimicamente , Idoso de 80 Anos ou mais , Fosfatase Alcalina/sangue , Biópsia , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Calcificação Fisiológica/efeitos dos fármacos , Carbonato de Cálcio/uso terapêutico , Colecalciferol/uso terapêutico , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Feminino , Fraturas do Fêmur/etiologia , Fíbula , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/induzido quimicamente , Doença Iatrogênica , Osteíte Deformante/complicações , Osteólise/sangue , Osteólise/induzido quimicamente , Osteólise/diagnóstico por imagem , Osteomalacia/sangue , Osteomalacia/tratamento farmacológico , Hormônio Paratireóideo/sangue , Cintilografia , Fraturas das Costelas/etiologia , Fraturas da Tíbia/etiologia , Ulna/patologia , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
CONTEXT: Sclerostin inhibits Wnt-ß-catenin signaling, regulating bone formation. Circulating sclerostin was reported to be elevated in X-linked hypophosphatemia (XLH) patients, and sclerostin antibody (Scl-Ab) increased bone mass and normalized circulating phosphate in Hyp mice. However, circulating sclerostin levels in patients with acquired hypophosphatemia due to tumor-induced osteomalacia (TIO) are rarely reported. OBJECTIVE: This study was designed to evaluate serum sclerostin levels in TIO patients compared with age- and sex-matched healthy controls and XLH patients to analyze correlations with bone mineral density (BMD) and laboratory parameters. METHODS: This cross-sectional study determined serum sclerostin levels in 190 individuals, comprising 83 adult TIO patients, 83 adult healthy controls and 24 adult XLH patients. RESULTS: TIO patients (43 male, 40 female) aged 44.3â ±â 8.7 (mean ± SD) years had lower levels of circulating sclerostin than controls (94.2â ±â 45.8 vs 108.4â ±â 42.3 pg/mL, Pâ =â 0.01), adjusted for age, gender, BMI, and diabetes rate. Sclerostin levels were positively associated with age (r =â 0.238, Pâ =â 0.030). Male patients had higher sclerostin than female patients (104.7â ±â 47.3 vs 83.0â ±â 41.8 pg/mL, Pâ =â 0.014). Sclerostin levels were positively associated with L1-4 BMD (r =â 0.255, Pâ =â 0.028), femoral neck BMD (r =â 0.242, Pâ =â 0.039), and serum calcium (r =â 0.231, Pâ =â 0.043). Comparison of sclerostin levels in TIO patients (nâ =â 24, age 35.9â ±â 7.3 years) vs XLH patients vs healthy controls revealed significant differences (respectively, 68.4â ±â 31.3, 132.0â ±â 68.8, and 98.6â ±â 41.1 pg/mL, Pâ <â 0.001). CONCLUSION: Circulating sclerostin was decreased in TIO patients but increased in XLH patients, possibly due to histological abnormality and bone mass.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , Raquitismo Hipofosfatêmico Familiar/sangue , Osteomalacia/sangue , Síndromes Paraneoplásicas/sangue , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Densidade Óssea , Cálcio/sangue , Cálcio/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Raquitismo Hipofosfatêmico Familiar/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Osteomalacia/metabolismo , Síndromes Paraneoplásicas/metabolismo , Via de Sinalização Wnt , Adulto JovemRESUMO
Fibroblast growth factor 23 (FGF23) is produced by bone and reduces serum phosphate by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption. Excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia while deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis. In addition, FGF23 has been shown to prevent the development of hyperphosphatemia during the progression of chronic kidney disease-mineral and bone disorder. Epidemiological studies have indicated that high FGF23 levels are associated with unfavorable events including higher mortality, cardiovascular events, progression of CKD and fracture; however, these associations are not observed unequivocally and it is not evident why they are present. While FGF23 has been shown to be a hormone that regulates phosphate metabolism, it remains to be established whether FGF23 has roles other than regulating mineral homeostasis.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hormônios/metabolismo , Animais , Fator de Crescimento de Fibroblastos 23 , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/metabolismo , Hipofosfatemia/sangue , Hipofosfatemia/metabolismo , Modelos Biológicos , Osteomalacia/sangue , Osteomalacia/metabolismo , Fosfatos/sangue , Fosfatos/metabolismoRESUMO
Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.
Assuntos
Neoplasias Ósseas/patologia , Fatores de Crescimento de Fibroblastos/sangue , Mesenquimoma/patologia , Ossos Metacarpais , Neoplasias de Tecido Conjuntivo/patologia , Osteomalacia/patologia , Neoplasias Ósseas/sangue , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/cirurgia , Feminino , Fator de Crescimento de Fibroblastos 23 , Seguimentos , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/diagnóstico por imagem , Hipofosfatemia/etiologia , Hipofosfatemia/patologia , Hipofosfatemia/cirurgia , Mesenquimoma/sangue , Mesenquimoma/complicações , Mesenquimoma/diagnóstico por imagem , Mesenquimoma/cirurgia , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/sangue , Neoplasias de Tecido Conjuntivo/complicações , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/cirurgia , Osteomalacia/sangue , Osteomalacia/diagnóstico por imagem , Osteomalacia/etiologia , Osteomalacia/cirurgia , Síndromes Paraneoplásicas , Fosfatos/sangue , RadiografiaRESUMO
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.
Assuntos
Hipofosfatemia/etiologia , Neoplasias Mandibulares/cirurgia , Osteomalacia/cirurgia , Síndromes Paraneoplásicas/cirurgia , Fosfatos/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/patologia , Neoplasias Mandibulares/sangue , Neoplasias Mandibulares/complicações , Neoplasias Mandibulares/patologia , Pessoa de Meia-Idade , Osteomalacia/sangue , Osteomalacia/patologia , Síndromes Paraneoplásicas/sangueRESUMO
OBJECTIVE: To investigate the clinical characteristics and surgical outcomes of sinonasal tumors associated with tumor-induced osteomalacia (TIO). STUDY DESIGN: Retrospective case series. SETTING: Single tertiary center. METHODS: We studied the clinical characteristics and surgical outcomes of 43 patients (22 male, 21 female) who had lesions in the nasal cavity and paranasal sinus associated with TIO and underwent surgery between August 2006 and November 2019. RESULTS: The mean ± SD duration between the onset of symptoms and surgery was 3.9 ± 2.6 years. The most common tumor site was the ethmoid sinus (76.7%), and the skull base was involved in 12 cases. Phosphaturic mesenchymal tumors were diagnosed in 41 patients, among whom there was 1 multifocal case. Another 2 cases involved odontogenic fibroma and hemangiofibroma, respectively. Serum phosphorus normalized in 39 cases within 4.4 ± 2.3 days, and serum fibroblastic growth factor 23 normalized within 1 day; clinical symptoms, however, gradually improved within several months after the first operation. There was no significant difference in the recovery rate between endoscopic and open surgery (P = 0.639). Two patients with recurrent cases and 2 with nonremission cases recovered after a sinonasal reoperation. The patient with a multifocal case recovered after the resection of the tumors in the ethmoid sinus and mandible. The overall recovery rate was 97.7%. CONCLUSION: Most sinonasal tumors associated with TIO are located in the ethmoid sinus, and the skull base is involved in some cases. Complete excision of the tumor leads to recovery, and endoscopic surgery could achieve recovery rates similar to those of open surgery.
Assuntos
Neoplasias Nasais/diagnóstico , Neoplasias Nasais/cirurgia , Osteomalacia/diagnóstico , Osteomalacia/cirurgia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/cirurgia , Adulto , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasais/sangue , Osteomalacia/sangue , Síndromes Paraneoplásicas/sangue , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Long-term therapy with antiepileptic drugs (AED) may be associated with increased total serum alkaline phosphatase (ALP) levels and reduced serum calcium, inorganic phosphorous, and vitamin D levels. These adverse biochemical alterations have an adverse effect on bone health. OBJECTIVE: To determine (a) onset of derangements in serum total ALP and its isoenzymes (liver, bone), calcium and 25-hydroxy vitamin D (25-OHD) concentrations after initiation of treatment with phenytoin or valproic acid monotherapy and (b) the effect of simultaneous supplementation with calcium and 25-OHD at recommended daily allowance (RDA) dosage, on these biochemical parameters. MATERIALS AND METHODS: Study was a prospective, case-controlled study in adults. Serum biochemical parameters were estimated at baseline, 30, 60, and 90 days of starting AED treatment in the study subjects: Groups--A (only calcium supplementation) and Group B (both calcium and 25-OHD supplementation). STATISTICAL ANALYSIS: Mean+/-SD, and students' paired t test (between groups A and B) unpaired students' t test (drug-wise). RESULTS: At 60 days of AED therapy Group A showed a significant increase in serum total ALP (78.83+/-11.04 to 101.75 +/- 9.56 IU/l) (P < 0.001), ALP-liver isoenzyme, (41.97+/- 10.81 to 68.83 +/-7.81 IU/L) (P < 0.001), significant decrease in calcium (9.30 +/- 0.36 to 8.80 +/- 0.38 mg%) (P < 0.001), ALP-bone isoenyzme (36.84 +/- 5.01 to 32.92 +/- 6.46 IU/L) (P < 0.001), and a significant decrease in 25-OHD (25.19 +/- 5.98 to 19.76 +/- 5.35 ng/ml) (P < 0.001) at 90 days. In contrast Group B, at 60 days, showed a significant decrease in serum total ALP (81.92 +/- 19.63 to 54.77. +/- 11.53 IU/L) (P < 0.0001), ALP-liver isoenzyme (48.01. +/- 13.53 to 28.12. +/- 5.88 IU/L) (P < 0.0001), significant increase in calcium ((9.24 +/- 0.31 to 9.93 +/- 0.26 mg%) (P < 0.001) and ALP-bone isoenzyme levels (33.93 +/- 12.2 to 26.25 +/- 8.23 IU/L). In Group B, 25-OHD levels showed a significant increase at 90 days (24.36 +/- 3.42 to 31.53 +/- 327 ng/ml) (P < 0.0001). CONCLUSION: Biochemical derangements in calcium metabolism involving the bone are seen by 60 days after starting AED monotherapy, indicating predisposition to development of osteomalacia in these patients. This is preventable by simultaneous oral supplementation with calcium and 25-OHD.
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Anticonvulsivantes/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Cálcio da Dieta/administração & dosagem , Osteomalacia/prevenção & controle , Fenitoína/efeitos adversos , Ácido Valproico/efeitos adversos , Vitamina D/administração & dosagem , Adulto , Fosfatase Alcalina/sangue , Cálcio/sangue , Método Duplo-Cego , Epilepsia/tratamento farmacológico , Feminino , Humanos , Índia , Masculino , Osteomalacia/sangue , Osteomalacia/induzido quimicamente , Estudos Prospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Vitamina D/sangue , Adulto JovemRESUMO
Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)(2)D(3) serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)(2)D(3) and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (-11%) and mineralized trabecular thickness (-18%) were low. The mean degree of mineralization of the bone matrix (-7%), the most frequent calcium concentration (-4.1%), and the amounts of fully mineralized bone (-40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets.