ABSTRACT
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.
Subject(s)
Fractures, Bone , Hypophosphatemia , Paraneoplastic Syndromes , Humans , Phosphates/therapeutic use , Hypophosphatemia/complications , Paraneoplastic Syndromes/diagnosis , Paraneoplastic Syndromes/etiology , Paraneoplastic Syndromes/therapy , Pain , Fibroblast Growth FactorsABSTRACT
BACKGROUND: Paradoxically, elderly persons with type 2 diabetes mellitus (T2DM) fracture despite having higher bone density than nondiabetics. Systemic factors associated with aging and T2DM may have detrimental, local effects on the skeleton. One such factor could be by altering the microenvironment of the mesenchymal stem cells (MSCs), multipotent progenitors capable of differentiating into adipocytes or osteoblasts. METHODS: Sera were obtained from four participant groups (n = 40 total, 10 per group): (1) young women with normal glucose tolerance (NGTY), (2) postmenopausal women with NGT), (3) postmenopausal women with impaired glucose tolerance (IGT), and (4) postmenopausal women with T2DM. Sera were incubated with human MSCs for 14 days. Cell proliferation and apoptosis were measured using EdU and TUNEL labeling assays, respectively. MSC differentiation for each group was determined using osteogenic and adipogenic gene expression markers quantified by qRT-PCR, as well as Alizarin Red and Oil Red O staining. RESULTS: Expression of adipogenic genes was greater than twofold higher (P < 0.05) in MSCs cultured with T2DM sera compared to those incubated with NGTY, NGT, or IGT sera. The increase in adipogenic gene expression corresponded with increased Oil Red O staining. Despite the increased adipogenic differentiation of MSCs exposed to T2DM sera, cell proliferation and apoptosis rates as well as osteoblastic activity were not significantly different among the four conditions. CONCLUSIONS: Systemic, circulating factors in the serum of older women with T2DM may promote MSC differentiation into adipocytes versus osteoblasts. Increased differentiation of MSCs into adipocytes is one possible mechanism by which T2DM increases fracture risk.
Subject(s)
Adipogenesis/physiology , Diabetes Mellitus, Type 2/blood , Glucose Intolerance/blood , Mesenchymal Stem Cells/metabolism , Osteogenesis/physiology , Aged , Apoptosis/physiology , Cell Line , Cell Proliferation/physiology , Cross-Sectional Studies , Female , Humans , Middle Aged , Postmenopause/bloodABSTRACT
CONTEXT: Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be non-specific and unrecognized, leading to long delays in diagnosis and treatment, which results in severe and progressive disability in patients with TIO. This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease. EVIDENCE ACQUISITION: A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO. EVIDENCE SYNTHESIS: In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (standard deviation) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery. CONCLUSION: TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.
ABSTRACT
BACKGROUND: In patients with X-linked hypophosphatemia (XLH), conventional therapy with oral phosphate salts and active vitamin D has been associated with nephrocalcinosis. However, the nature of the relationships among XLH, its treatment, nephrocalcinosis, and kidney function remain poorly understood. METHODS: Renal ultrasounds were performed and glomerular filtration rates were estimated (eGFR) at baseline in burosumab-naïve patients with XLH who participated in burosumab clinical trials (NCT02181764, NCT02526160, NCT02537431, NCT02163577, NCT02750618, NCT02915705) or enrolled in the XLH Disease Monitoring Program (XLH-DMP; NCT03651505). In this cross-sectional analysis, patient, disease, and treatment characteristics were described among patients with and without nephrocalcinosis. RESULTS: The analysis included 196 children (mean [SD] age 7.6 [4.0] years) and 318 adults (40.3 [13.1] years). Mean (SD) height z-score was -1.9 (1.2) for children and -2.3 (1.7) for adults. Nearly all children (97%) and adults (94%) had previously received conventional therapy. Nephrocalcinosis was detected in 22% of children and 38% of adults. In children, reduced eGFR <90 ml/min/1.73 m2 was more prevalent in those with nephrocalcinosis (25%) than in those without (11%), a finding that was not observed in adults. Children with nephrocalcinosis had lower mean values of TmP/GFR (P<.05), serum 1,25(OH)2D (P<.05), and eGFR (P<.001) and higher mean serum calcium concentrations (P<.05) than did those without nephrocalcinosis. Adults with nephrocalcinosis had lower mean serum phosphorus (P<.01) and 1,25(OH)2D (P<.05) concentrations than those without. Exploratory logistic regression analyses revealed no significant associations between the presence of nephrocalcinosis and other described patient or disease characteristics. CONCLUSIONS: Nephrocalcinosis was observed in nearly one quarter of children and more than one-third of adults with XLH. Further study is needed to better understand the predictors and long-term consequences of nephrocalcinosis, with surveillance for nephrocalcinosis remaining important in the management of XLH.
BACKGROUND: Conventionally, patients with X-linked hypophosphatemia (XLH) were treated with phosphate and vitamin D taken by mouth. However, this therapy might lead to a buildup of calcium in the kidney, called nephrocalcinosis. Here, we tried to better understand how XLH, conventional therapy, nephrocalcinosis, and kidney function are related. METHODS: Nephrocalcinosis was detected with kidney ultrasounds. Kidney function, called the estimated glomerular filtration rate (eGFR), was determined using the blood level of creatinine. Patients had been part of burosumab clinical trials or part of the XLH Disease Monitoring Program. Data were collected from patients before they received burosumab. RESULTS: The study included 196 children and 318 adults. Almost all children and adults had received conventional therapy. 22% of children had nephrocalcinosis and 38% of adults had nephrocalcinosis. In children, low eGFR was more common in those with nephrocalcinosis (25%) than in those without (11%). In adults, levels of eGFR were similar among those with and without nephrocalcinosis.Some lab values were different among patients with versus those without nephrocalcinosis. Children with nephrocalcinosis had significantly greater loss of phosphate by the kidneys, lower blood levels of the active form of vitamin D (1,25(OH)2D), lower eGFR, and higher blood levels of calcium than those without nephrocalcinosis. Adults with nephrocalcinosis had significantly lower blood levels of phosphorus and 1,25(OH)2D concentrations than those without. CONCLUSIONS: Nearly one quarter of children and more than one-third of adults with XLH, most of whom had received conventional therapy, had nephrocalcinosis. Further study is needed to better understand what factors can predict who will get nephrocalcinosis and to understand the long-term consequences of nephrocalcinosis. It remains important to monitor patients with XLH for nephrocalcinosis.
ABSTRACT
Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused by tumors that secrete fibroblast growth factor 23, leading to chronic hypophosphatemia, poor skeletal health, and impaired physical function. In a phase 2 trial (UX023T-CL201; NCT02304367; n = 14), 48 weeks of burosumab treatment restored phosphate homeostasis, with improvements in skeletal health, functional mobility, and patient-reported pain, fatigue, and health-related quality of life (HRQL) (SF-36 v2). Here, we report an exploratory mixed-methods analysis of change from baseline after 144 weeks of burosumab treatment alongside qualitative data from exit interviews with 8 of 14 trial participants to evaluate meaningful treatment effects from a patient perspective. The interview subset (n = 8) reported pain and fatigue and compromised HRQL at baseline. In the interviews, participants reported that compromised HRQL and pain were the most important aspects of the disease to treat; both were considered more bothersome than fatigue and compromised physical function and activities of daily living. Improvements in pain and fatigue after treatment were reported, some of which achieved statistically and/or clinically meaningful thresholds. Furthermore, improvements in SF-36 v2 scores were most pronounced in the Physical Component Score and its Physical Function and Bodily Pain domains. Overall, the interview subset provided descriptions of symptomatic improvement and its clinical meaningfulness, including physical function, participation in activities of daily living, and mental well-being. Thus, this exploratory mixed-methods analysis provides deeper understanding of patients' perception of clinical meaningfulness beyond that articulated in validated patient-reported outcome instruments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Subject(s)
Osteomalacia , Quality of Life , Humans , Adult , Activities of Daily Living , Osteomalacia/drug therapy , Fatigue/drug therapy , Fatigue/etiology , Pain , Minerals , Patient Reported Outcome Measures , Fibroblast Growth FactorsABSTRACT
Persons with type 2 diabetes mellitus (T2DM) are at increased risk for hip fracture despite normal bone mineral density (BMD). The contribution of body composition to hip geometry, a measure of hip strength, has not been studied in T2DM. We hypothesized that lean mass would predict hip geometry. Subjects (n=134) for this cross-sectional analysis were men and women aged 56 ± 6yr with non-insulin-requiring T2DM. Fat and lean mass were measured with dual-energy X-ray absorptiometry (DXA). Abdominal fat was measured with magnetic resonance imaging. Hip geometry parameters including section modulus, cross-sectional area, and buckling ratio were estimated from DXA using validated formulae. Subjects had normal BMD, elevated body mass indices (29-41 kg/m(2)), and controlled T2DM (hemoglobin A1c: 5.1-8.3%). In bivariate analysis, lean mass was positively associated with section modulus and cross-sectional area in both sexes (r=0.36-0.55, p<0.05). In multivariate analyses, lean mass remained a significant predictor of all hip strength estimates in both sexes. In women alone, fat mass predicted parameters of hip strength. These data demonstrate that lean mass is significantly associated with hip strength in subjects with non-insulin-requiring T2DM. Resistance exercises that build lean mass may be an intervention for hip fracture prevention in T2DM, although additional research is needed.
Subject(s)
Absorptiometry, Photon , Body Mass Index , Bone Density , Diabetes Mellitus, Type 2/diagnostic imaging , Hip Joint/diagnostic imaging , Adiposity , Adult , Aged , Body Composition , Female , Humans , Male , Middle AgedABSTRACT
The development of coronavirus disease 2019 (COVID-19) vaccines has proceeded at an unprecedented pace, with numerous trials conducted simultaneously across the world as a result of massive technological and financial resource expenditures. With multiple vaccines having now received regulatory approval, public health efforts to promote widespread vaccine dissemination are currently underway. There has been particular emphasis placed on vaccination of older populations, the age group in which COVID-19 infection has been most lethal. However, such widespread vaccination approaches have necessarily raised important questions related to potential interactions with underlying diseases and concomitant treatments among persons to be vaccinated. Osteoporosis is a chronic condition marked by reduced bone strength and an associated increased risk for fracture that generally requires sustained medical intervention(s). Osteoporosis is neither associated with a higher risk of COVID-19 infection nor by more pronounced disease severity following infection, such that individuals with osteoporosis need not be more highly prioritized for COVID-19 vaccination. Osteoporosis therapies do not interfere with the efficacy or side effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Depending on the specific drug profile within an anti-osteoporosis medication category, minor adjustments to the timing of drug administration may be considered with respect to the patient's COVID-19 vaccination schedule. Herein we provide practical recommendations for the care of patients requiring treatment for osteoporosis in the setting of COVID-19 vaccination. © 2021 American Society for Bone and Mineral Research (ASBMR).
Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Osteoporosis/drug therapy , Humans , United States , VaccinationABSTRACT
Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.
Subject(s)
Hypophosphatemia , Neoplasms, Connective Tissue , Osteomalacia , Paraneoplastic Syndromes , Fibroblast Growth Factor-23 , Fibroblast Growth Factors , Humans , Hypophosphatemia/etiology , Hypophosphatemia/therapy , Neoplasms, Connective Tissue/complications , Osteomalacia/etiology , Osteomalacia/therapyABSTRACT
Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
Subject(s)
Osteomalacia , Quality of Life , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Fibroblast Growth Factor-23 , Fibroblast Growth Factors , Humans , Osteomalacia/drug therapy , Paraneoplastic SyndromesABSTRACT
BACKGROUND: The aim of this paper is to describe the utility of various recruitment modalities utilized in the Working to Increase Stability through Exercise (WISE) study. WISE is a pragmatic randomized trial that is testing the impact of a 3-year, multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers or delivered via DVD on the rate of serious fall-related injuries among adults 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The modified goal was to recruit 1130 participants over 2 years in three regions of Pennsylvania. METHODS: The at-risk population was identified primarily using letters mailed to patients of three health systems and those over 65 in each region, as well as using provider alerts in the health record, proactive recruitment phone calls, radio advertisements, and presentations at community meetings. RESULTS: Over 24 months of recruitment, 209,301 recruitment letters were mailed, resulting in 6818 telephone interviews. The two most productive recruitment methods were letters (72% of randomized participants) and the research registries at the University of Pittsburgh (11%). An average of 211 letters were required to be mailed for each participant enrolled. Of those interviewed, 2854 were ineligible, 2,825 declined to enroll and 1139 were enrolled and randomized. Most participants were female (84.4%), under age 75 (64.2%), and 50% took an osteoporosis medication. Not having a prior fragility fracture was the most common reason for not being eligible (87.5%). The most common reason provided for declining enrollment was not feeling healthy enough to participate (12.6%). CONCLUSIONS: The WISE study achieved its overall recruitment goal. Bulk mailing was the most productive method for recruiting community-dwelling older adults at risk of serious fall-related injury into this long-term physical activity intervention trial, and electronic registries are important sources and should be considered.
Subject(s)
Accidental Falls , Exercise , Accidental Falls/prevention & control , Aged , Exercise Therapy , Female , Health Services , Humans , Risk FactorsABSTRACT
Phosphorus is an essential element in skeletal development, bone mineralization, membrane composition, nucleotide structure, and cellular signaling. Phosphate, the principal form in which phosphorus is found in the body, is regulated by the complex interplay of the hormones parathyroid hormone (PTH), calcitriol (1,25[OH](2) vitamin D(3)), and fibroblast growth factor 23 (FGF23). These collectively govern bone mineralization, absorption of phosphorus by the intestine, and renal tubular reabsorption of phosphate. The skeleton is the major storage pool for phosphate and the principal production site for FGF23, a major phosphate regulatory hormone. Recent advances in understanding the molecular basis of disorders of phosphate metabolism have revealed new phosphate-regulatory hormones and provided insight into how these regulators may interface with previously known phosphate-regulatory pathways. Here we outline the current knowledge about the regulation of normal phosphate homeostasis and present a review of the molecular basis of disorders of phosphate homeostasis.
Subject(s)
Bone and Bones/metabolism , Homeostasis/physiology , Phosphates/metabolism , Bone Density , Calcitriol/metabolism , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/metabolism , Humans , Parathyroid Hormone/metabolismABSTRACT
Approximately one-third of older adults fall each year and fall-related injuries are a leading cause of death and disability among this rapidly expanding age group. Despite the availability of bisphosphonates to reduce fractures, concerns over side effects have dramatically reduced use, suggesting that other treatment options are needed. Though many smaller studies have shown that physical activity programs can reduce falls, no study has been adequately powered to detect a reduction in fall-related injuries. We present the design of a three-year randomized controlled clinical trial of 1130 adults age 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The main aim is to determine the impact of a community-based multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers (or delivered via DVD) and accompanied by coaching and oversight, by telephone and in-person, by a fitness professional. The main outcome measure is serious fall-related injuries. Secondary outcomes include health care utilization, bone and muscle mass, loneliness, health-related quality of life and mood. The study represents the first large clinical trial of a comprehensive physical activity program to reduce secondary injuries among patients with a history of fragility fracture.
Subject(s)
Accidental Falls/prevention & control , Exercise Therapy/methods , Osteoporotic Fractures/prevention & control , Postural Balance , Wounds and Injuries/prevention & control , Absorptiometry, Photon , Affect , Aged , Aged, 80 and over , Bone Density , Emergency Service, Hospital/statistics & numerical data , Exercise , Female , Health Services/statistics & numerical data , Hospitalization/statistics & numerical data , Humans , Loneliness , Male , Quality of Life , Resistance Training/methodsABSTRACT
Tumors associated with osteomalacia elaborate the novel factor(s), phosphatonin(s), which causes phosphaturia and hypophosphatemia by cAMP-independent pathways. We show that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, is a circulating phosphaturic factor that antagonizes renal Wnt-signaling. In cultured opossum renal epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of sFRP-4 in normal rats over 2 hours specifically increased renal fractional excretion of inorganic phosphate (FEPi) from 14% +/- 2% to 34% +/- 5% (mean +/- SEM, P < 0.01). Urinary cAMP and calcium excretion were unchanged. In thyro-parathyroidectomized rats, sFRP-4 increased FEPi from 0.7% +/- 0.2% to 3.8% +/- 1.2% (P < 0.05), demonstrating that sFRP-4 inhibits renal inorganic phosphate reabsorption by PTH-independent mechanisms. Administration of sFRP-4 to intact rats over 8 hours increased FEPi, decreased serum phosphate (1.95 +/- 0.1 to 1.53 +/- 0.09 mmol/l, P < 0.05) but did not alter serum 1alpha, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1alpha-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal beta-catenin and increased phosphorylated beta-catenin concentrations. The sFRP-4 is detectable in normal human serum and in the serum of a patient with tumor-induced osteomalacia. Thus, sFRP-4 displays phosphatonin-like properties, because it is a circulating protein that promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1alpha, 25-dihydroxyvitamin D.
Subject(s)
Kidney/metabolism , Osteomalacia/metabolism , Paraneoplastic Syndromes/metabolism , Phosphates/metabolism , Proto-Oncogene Proteins/physiology , Zebrafish Proteins , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Animals , Calcitriol/blood , Cytochrome P-450 Enzyme System/genetics , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/physiology , Humans , Opossums , Proto-Oncogene Proteins/antagonists & inhibitors , Rats , Sodium/metabolism , Sodium-Phosphate Cotransporter Proteins , Steroid Hydroxylases/genetics , Symporters/physiology , Vitamin D/metabolism , Vitamin D3 24-Hydroxylase , Wnt ProteinsABSTRACT
Fibroblast growth factor 23 (FGF23) is an important regulator of phosphate and vitamin D metabolism and its excessive or insufficient production leads to a wide variety of skeletal disorders. This article reviews the FGF23-α-Klotho signaling pathway, highlighting the latest developments in FGF23 regulation and action, and describes the disorders associated with FGF23 excess or deficiency.
Subject(s)
Bone Diseases/metabolism , Fibroblast Growth Factors/metabolism , Glucuronidase/metabolism , Signal Transduction , Fibroblast Growth Factor-23 , Humans , Klotho Proteins , Phosphates/metabolism , Vitamin D/metabolismABSTRACT
Consumptive hypothyroidism is characterized by excessive inactivation of thyroid hormone by type 3 iodothyronine deiodinase (D3). Previously this rare syndrome was described in association with massive hemangiomas in children and in a single case of a hemangioendothelioma in an adult. Here we report the first case of consumptive hypothyroidism from a nonvascular tumor in a patient who required supraphysiologic doses of levothyroxine prior to the resection of a large malignant solitary fibrous tumor. The tumor expressed D3 message, protein and exhibited functional D3 enzymatic activity. The clinical presentation of this patient expands the differential diagnosis of hypothyroidism, adds to the growing list of paraneoplastic syndromes that impact the endocrine system, and extends the spectrum of tumor types associated with consumptive hypothyroidism.
Subject(s)
Hypothyroidism/etiology , Iodide Peroxidase/biosynthesis , Paraneoplastic Syndromes/etiology , Thyroid Neoplasms/enzymology , Humans , Male , Middle AgedABSTRACT
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic form of renal phosphate wasting that results in severe hypophosphatemia, a defect in vitamin D metabolism, and osteomalacia. This debilitating disorder is illustrated by the clinical presentation of a 55-year-old woman with progressive fatigue, weakness, and muscle and bone pain with fractures. After a protracted clinical course and extensive laboratory evaluation, tumor-induced osteomalacia was identified as the basis of her clinical presentation. In this article, the distinctive clinical characteristics of this syndrome, the advances in diagnosis of TIO, and new insights into the pathophysiology of this disorder are discussed.
Subject(s)
Osteomalacia/etiology , Paraneoplastic Syndromes/physiopathology , Diagnosis, Differential , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/genetics , Homeostasis , Humans , Kidney/metabolism , Middle Aged , Neoplasms/complications , Osteomalacia/diagnosis , Osteomalacia/therapy , Paraneoplastic Syndromes/diagnosis , Paraneoplastic Syndromes/therapy , Phosphates/metabolism , Vitamin D/metabolismABSTRACT
Pseudohypoparathyroidism (PHP) is characterized by biochemical hypoparathyroidism with elevated parathyroid hormone levels owing to reduced target tissue responsiveness to parathyroid hormone. Patients with PHP la have somatic defects termed Albright's hereditary osteodystrophy (AHO) and exhibit resistance to additional hormones because of heterozygous mutations in the GNAS1 gene that lead to a generalized deficiency of the a subunit of Gs, the heterotrimeric G protein that couples receptors to adenylyl cyclase. By contrast, patients with PHP 1b lack AHO and have selective parathyroid hormone (PTH) resistance, presumably because of an imprinting defect that impairs expression of G(s)alpha in the proximal renal tubule. Although an epigenetic defect in GNAS1 has been identified in subjects with PHP1b, the genetic defect is unknown. To define the genetic defect in PHP 1b, we performed a genome-wide linkage analysis in five multi-generational PHP lb families. Of the 408 polymorphic microsatellite markers examined, markers located on chromosome 20q13.3, the region containing GNAS1, demonstrated linkage to PHP lb. Fine-mapping and multipoint linkage analysis of this region demonstrated linkage to a 5.7-cM region between 907rep2 and the telomere. Haplotype analysis established that affected individuals shared a 5-cM region including part of the GNAS1 gene to the telomere. Our data confirm that PHP1b is linked to a region that includes GNAS1, and further refine the locus, although the primary genetic mutation(s) that causes defective imprinting of GNAS1 remains undefined.
Subject(s)
Chromosomes, Human, Pair 20 , GTP-Binding Protein alpha Subunits, Gs/genetics , Genetic Linkage , Pseudohypoparathyroidism/genetics , Base Sequence , Chromosome Mapping , DNA Primers , Female , Humans , Male , PedigreeABSTRACT
Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS1, the gene encoding the alpha-chain of G(s), and is associated with short stature, obesity, brachydactyly, and sc ossifications. AHO patients with GNAS1 mutations on maternally inherited alleles also manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to paternal imprinting of G alpha(s) transcripts in specific tissues. Recent evidence has shown that G alpha(s) transcripts are also imprinted in the pituitary somatotrophs that secrete GH. Because this imprinting could influence GHRH-dependent stimulation of somatotrophs, we hypothesized that maternally inherited GNAS1 mutations would impair GH secretion. We studied GH status in 13 subjects with PHP type 1a. GH responses to arginine/L-dopa and arginine/GHRH were deficient in nine subjects, all of whom were obese and had low serum concentrations of IGF-I. By contrast, none of the four GH-sufficient subjects were obese, and all had normal IGF-I levels. Our data indicate that GH deficiency is common (69%) in PHP type 1a and may contribute to the obesity and short stature typical of AHO. We propose that GH status be evaluated in all patients with PHP type 1a.