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Jornal Brasileiro de Nefrologia 2024Renal osteodystrophy (ROD) refers to a group of bone morphological patterns that derive from distinct pathophysiological mechanisms. Whether the ROD subtypes influence...
INTRODUCTION
Renal osteodystrophy (ROD) refers to a group of bone morphological patterns that derive from distinct pathophysiological mechanisms. Whether the ROD subtypes influence long-term outcomes is unknown. Our objective was to explore the relationship between ROD and clinical outcomes.
METHODS
This study is a subanalysis of the Brazilian Registry of Bone Biopsies (REBRABO). Samples from individual patients were classified as having osteitis fibrosa (OF), mixed uremic osteodystrophy (MUO), adynamic bone disease (ABD), osteomalacia (OM), normal/minor alterations, and according to turnover/mineralization/volume (TMV) system. Patients were followed for 3.4 yrs. Clinical outcomes were: bone fractures, hospitalization, major adverse cardiovascular events (MACE), and death.
RESULTS
We enrolled 275 participants, of which 248 (90%) were on dialysis. At follow-up, 28 bone fractures, 97 hospitalizations, 44 MACE, and 70 deaths were recorded. ROD subtypes were not related to outcomes.
CONCLUSION
The incidence of clinical outcomes did not differ between the types of ROD.
Topics: Humans; Renal Dialysis; Chronic Kidney Disease-Mineral and Bone Disorder; Prospective Studies; Bone and Bones; Fractures, Bone
PubMed: 37947359
DOI: 10.1590/2175-8239-JBN-2023-0119en -
JCI Insight Dec 2023Fibroblast growth factor 23 (FGF23) is a phosphate-regulating (Pi-regulating) hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23...
Fibroblast growth factor 23 (FGF23) is a phosphate-regulating (Pi-regulating) hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth, and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone-specific deletion of Fgf23 on bone and mineral metabolism in the dentin matrix protein 1-knockout (Dmp1KO) mouse model of ARHR. At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency contributed to impaired mineralization independent of FGF23 or Pi levels. In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.
Topics: Animals; Mice; Calcification, Physiologic; Extracellular Matrix Proteins; Familial Hypophosphatemic Rickets; Fibroblast Growth Factors; Hypophosphatemia; Mice, Knockout; Minerals; Osteomalacia
PubMed: 37943605
DOI: 10.1172/jci.insight.156850 -
Orthopaedic Surgery Dec 2023Tumor-induced osteomalacia (TIO) belongs to a rare disease of the paraneoplastic syndrome. Phosphate uric mesenchymal tumor (PMT) is the most common cause of TIO, while... (Review)
Review
BACKGROUND
Tumor-induced osteomalacia (TIO) belongs to a rare disease of the paraneoplastic syndrome. Phosphate uric mesenchymal tumor (PMT) is the most common cause of TIO, while the possibility of other tumors cannot be excluded.
CASE PRESENTATION
We present a case of a 36-year-old female patient with systemic skeletal abnormalities. The woman complained of low back pain with mild motor dysfunction for 2 years. Laboratory examination showed abnormalities in markers of bone metabolism, parathyroid hormone (PTH), vitamin D and serum phosphorus. Pooled imaging examination indicated extension abnormalities in the skeletal system and a single lesion in the right femoral head. The lesion of the right femoral was imaging with somatostatin receptor-positive, which was highly suggestive of a single neuroendocrine tumor. CT guided right femoral tumorectomy and bone grafting were performed when medical treatment failed. Postoperative pathological diagnosis was phosphate urinary mesenchymal tumor secreting fibroblast growth factor 23 (FGF23), which accorded with pre-operative expectations. The postoperative symptoms were effectively relieved, and indicators returned to normal.
CONCLUSION
The tumors causing TIO exhibited significant heterogeneity in terms of tissue origin, pathological characteristics and biological behavior, but the unique common characteristic is the secretion of FGF23. With significant progress in diagnosis and treatment, the clinical follow-up of most TIO patients shows a good prognosis, but the prognosis of those with malignant tumors is relatively poor.
Topics: Female; Humans; Adult; Fibroblast Growth Factors; Phosphates; Paraneoplastic Syndromes; Osteomalacia
PubMed: 37933469
DOI: 10.1111/os.13901 -
Endocrinology, Diabetes & Metabolism... Jan 2023Tumour-induced osteomalacia (TIO) is due to an overproduction of fibroblast growth factor 23 (FGF23) by mesenchymal tumours, causing hypophosphatemia, osteomalacia and...
SUMMARY
Tumour-induced osteomalacia (TIO) is due to an overproduction of fibroblast growth factor 23 (FGF23) by mesenchymal tumours, causing hypophosphatemia, osteomalacia and muscle weakness. TIO is usually cured by tumour resection, but neoplasms may be unidentifiable and unresectable or the patient may refuse surgery. In these cases, medical treatment with oral phosphate and calcitriol is mandatory, but it is not fully effective and it is associated with low compliance. Burosumab, a human MAB against FGF23 employed to treat X-linked hypophosphatemia (XLH), has recently been approved for TIO in the USA. Maximum burosumab dose in XLH is 90 mg administered for 2 weeks; there are no data on clinical efficacy and safety of this dose in TIO. We reported the case of a 73 years old male with multiple non-traumatic fractures, low bone mineral density, pain and reduced independence of activities of daily living. Biochemical evaluation showed hypophosphatemia, high alkaline phosphatase (ALP) and C-terminal telopeptide (CTX) and normal albumin-corrected total calcium and parathyroid hormone. Tubular phosphate reabsorption was low (80%), whereas C-terminal tail of FGF23 (cFGF23) was elevated. A 68Ga-DOTATOC PET was performed, identifying a lesion in the first left rib. The patient refused surgery; therefore, burosumab therapy was started. After 18 months of treatment (maximum dose: 60 mg administered for 2 weeks), plasma phosphate normalized and ALP levels improved (138 U/L). Patient clinical symptoms as well as pain severity and fatigue improved. Neither adverse events nor tumour progression was reported during follow-up except for a painless fracture of the second right rib.
LEARNING POINTS
Our case shows efficacy and safety of burosumab treatment administered every 2 weeks in a tumour-induced osteomalacia (TIO) patient. After 18 months of treatment at a maximum dose of 60 mg every 2 weeks, we found plasma phosphate normalization and ALP reduction as well as improvement in clinical symptoms and fatigue. Neither adverse events nor tumour progression was reported during follow-up, except for a painless fracture of the second right rib.
PubMed: 37931408
DOI: 10.1530/EDM-22-0317 -
JCEM Case Reports Jul 2023Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with tumors secreting fibroblast growth factor 23 that can be cured with complete surgical...
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with tumors secreting fibroblast growth factor 23 that can be cured with complete surgical resection of the tumor. However, when these tumors are at difficult locations, less invasive modalities such as thermal ablation (TA) might be a good alternative. A 40-year-old woman was seen for a second opinion because of severe hypophosphatemia with complaints of fatigue, myalgia, and muscle weakness for which she needed IV phosphate for 15 to 18 hours per day in addition to oral alfacalcidol and phosphate. Initial laboratory results revealed hypophosphatemia (0.59 mmol/L [1.83 mg/dL]; reference range, 0.90-1.50 mmol/L [8.40-10.2 mg/dL]), increased fibroblast growth factor 23 levels (137 RU/mL; reference range, <125 RU/mL), and a reduced TmP-GFR (0.47 mmol/L; reference range, 0.8-1.4 mmol/L). Gallium-positron emission tomography/computed tomography (CT) showed moderately increased uptake at thoracic vertebra (Th) 8 and mildly increased uptake at Th7, suggestive of TIO. Complete tumor removal would have required resection of at least 1 vertebral body. Therefore, CT-guided TA was performed at Th8. No complications were observed, and in the months after, treatment with IV phosphate could be discontinued, indicating a satisfying result from the procedure. This extreme TIO case demonstrates that CT-guided TA can be an alternative to extensive or risky classical surgery.
PubMed: 37908985
DOI: 10.1210/jcemcr/luad086 -
JCEM Case Reports Jul 2023Vitamin D hydroxylation-deficient rickets type 1A is an autosomal recessive disorder caused by pathogenic variants in gene, which encodes for 1α-hydroxylase, the...
Vitamin D hydroxylation-deficient rickets type 1A is an autosomal recessive disorder caused by pathogenic variants in gene, which encodes for 1α-hydroxylase, the enzyme responsible for the conversion of 25-OH vitamin D into its active form 1,25(OH)2 vitamin D. We report the case of a 3-year-old female Mexican patient with growth retardation and progressive bone deformity, whose laboratory studies showed 25-OH vitamin D deficiency, a normal serum calcium and an elevated intact parathyroid hormone level that remained high despite calcitriol, cholecalciferol, and calcium supplementation. Tc sestamibi gammagram showed findings suggestive of parathyroid hyperplasia. Bone histomorphometry showed an image consistent with hyperparathyroidism without findings of osteomalacia, so normocalcemic primary hyperparathyroidism was suspected and a subtotal parathyroidectomy was performed, with the patient developing postoperative hypoparathyroidism. When she arrived at our clinic at age 18 years, she showed calcium- and calcitriol-dependent hypocalcemia, with secondary hyperparathyroidism and low levels of 1,25(OH)2 vitamin D in the absence of a 25-OH vitamin D deficiency, reflecting a defect in 1α-hydroxylation. Molecular testing revealed compound heterozygous variants in gene. This is the first reported case of an inherited disorder of vitamin D metabolism that was diagnosed and surgically treated as primary hyperparathyroidism.
PubMed: 37908980
DOI: 10.1210/jcemcr/luad084 -
Annual Review of Pathology Jan 2024The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate... (Review)
Review
The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.
Topics: Adult; Humans; Middle Aged; Phosphoric Diester Hydrolases; Vascular Calcification; Pyrophosphatases
PubMed: 37871131
DOI: 10.1146/annurev-pathmechdis-051222-121126 -
Indian Journal of Endocrinology and... 2023
PubMed: 37867990
DOI: 10.4103/ijem.ijem_125_23 -
International Medical Case Reports... 2023Tumor-induced osteomalacia (TIO) can cause osteomalacia due to excessive production of fibroblast growth factor 23 (FGF23) by the tumor. Since TIO is a very rare...
Tumor-induced osteomalacia (TIO) can cause osteomalacia due to excessive production of fibroblast growth factor 23 (FGF23) by the tumor. Since TIO is a very rare disease, it is often misdiagnosed as intervertebral disc herniation, spondyloarthritis, or osteoporosis. We report a 65-year-old man who developed generalized arthralgia and difficulty walking two years ago and was diagnosed with multiple fractures throughout his body. He was initially diagnosed with osteoporosis and was treated with calcitriol. However, he was referred to our hospital since his symptoms did not improve. We diagnosed tumor-induced osteomalacia based on low serum phosphorus, high bone-type alkaline phosphatase, high FGF23 levels, and the presence of two tumors. The responsible tumor was identified using FGF23 levels in venous sampling. As the location of the tumor made surgical resection difficult, we selected treatment with burosumab, a human monoclonal antibody against FGF23, leading to improvement in the hypophosphatemia and pain, such that he was able to walk with a cane. In cases of osteoporosis with hypophosphatemia, general physicians should keep TIO in mind, and attempt to identify the responsible tumor lesion.
PubMed: 37840970
DOI: 10.2147/IMCRJ.S425599