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Journal of Bone and Mineral Research :... Apr 2021Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate...
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..
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Osteomalacia; Paraneoplastic Syndromes; Quality of Life
PubMed: 33338281
DOI: 10.1002/jbmr.4233 -
Progress in Biophysics and Molecular... Sep 2006Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After... (Review)
Review
Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein. After transcription and translation the protein is formed, e.g. osteocalcin or calcium binding protein. The calcium binding protein mediates calcium absorption from the gut. The production of 1,25(OH)2D is stimulated by parathyroid hormone (PTH) and decreased by calcium. Risk factors for vitamin D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age. Risk groups are immigrants and the elderly. Vitamin D status is dependent upon sunshine exposure but within Europe, serum 25(OH)D levels are higher in Northern than in Southern European countries. Severe vitamin D deficiency causes rickets or osteomalacia, where the new bone, the osteoid, is not mineralized. Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures. A negative relationship exists between serum 25(OH)D and serum PTH. The threshold of serum 25(OH)D, where serum PTH starts to rise is about 75nmol/l according to most surveys. Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents. The effects of 1,25(OH)2D and the vitamin D receptor have been investigated in patients with genetic defects of vitamin D metabolism and in knock-out mouse models. These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential. On the other side, bone mineralization can occur by high ambient calcium concentration, so by high doses of oral calcium or calcium infusion. The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP. The latter responses are very rapid and include the effects on the pancreas, vascular smooth muscle and monocytes. Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance. The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. Active calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact vitamin D receptor. Bone mineralization mainly depends on ambient calcium concentration. Vitamin D metabolites may play a role in the prevention of auto-immune disease and cancer.
Topics: Animals; Bone Diseases; Calcium; Genetic Predisposition to Disease; Humans; Skin; Ultraviolet Therapy; Vitamin D; Vitamin D Deficiency
PubMed: 16563471
DOI: 10.1016/j.pbiomolbio.2006.02.016 -
Insights Into Imaging Mar 2021Osteoid osteoma is a painful, benign and common bone tumor that is prevalent in young adults. The typical clinical presentation consists of pain that becomes worse at... (Review)
Review
Osteoid osteoma is a painful, benign and common bone tumor that is prevalent in young adults. The typical clinical presentation consists of pain that becomes worse at night and is relieved by nonsteroidal anti-inflammatory drugs. The most common imaging finding is a lytic lesion, known as a nidus, with variable intralesional mineralization, accompanied by bone sclerosis, cortical thickening and surrounding bone marrow edema, as well as marked enhancement with intravenous contrast injection. When the lesion is located in typical locations (intracortical bone and the diaphyses of long bones), both characteristic clinical and radiological features are diagnostic. However, osteoid osteoma is a multifaceted pathology that can have unusual presentations, such as intraarticular osteoid osteoma, epiphyseal location, lesions at the extremities and multicentric nidi, and frequently present atypical clinical and radiological manifestations. In addition, many conditions may mimic osteoid osteoma and vice versa, leading to misdiagnosis. Therefore, it is essential to understand these musculoskeletal diseases and their imaging findings to increase diagnostic accuracy, enable early treatment and prevent poor prognosis.
PubMed: 33683492
DOI: 10.1186/s13244-021-00978-8 -
Journal of Nanobiotechnology Aug 2023Stabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) can directly increase cancellous bone formation and play an essential role in bone...
BACKGROUND
Stabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) can directly increase cancellous bone formation and play an essential role in bone modeling and remodeling. However, whether an increased HIF-1α expression in adipose-derived stem cells (ADSCs) increases osteogenic capacity and promotes bone regeneration is not known.
RESULTS
In this study, ADSCs transfected with small interfering RNA and HIF-1α overexpression plasmid were established to investigate the proliferation, migration, adhesion, and osteogenic capacity of ADSCs and the angiogenic ability of human umbilical vein endothelial cells (HUVECs). Overexpression of HIF-1α could promote the biological functions of ADSCs, and the angiogenic ability of HUVECs. Western blotting showed that the protein levels of osteogenesis-related factors were increased when HIF-1α was overexpressed. Furthermore, the influence of upregulation of HIF-1α in ADSC sheets on osseointegration was evaluated using a Sprague-Dawley (SD) rats implant model, in which the bone mass and osteoid mineralization speed were evaluated by radiological and histological analysis. The overexpression of HIF-1α in ADSCs enhanced bone remodeling and osseointegration around titanium implants. However, transfecting the small interfering RNA (siRNA) of HIF-1α in ADSCs attenuated their osteogenic and angiogenic capacity. Finally, it was confirmed in vitro that HIF-1α promotes osteogenic differentiation and the biological functions in ADSCs via the VEGF/AKT/mTOR pathway.
CONCLUSIONS
This study demonstrates that HIF-1α has a critical ability to promote osteogenic differentiation in ADSCs by coupling osteogenesis and angiogenesis via the VEGF/AKT/mTOR signaling pathway, which in turn increases osteointegration and bone formation around titanium implants.
Topics: Animals; Humans; Rats; Human Umbilical Vein Endothelial Cells; Neovascularization, Physiologic; Osteogenesis; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; RNA, Small Interfering; Signal Transduction; Titanium; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37550736
DOI: 10.1186/s12951-023-02020-z -
Autopsy & Case Reports 2022Osteosarcoma of the jaw represents less than 1% of all head and neck malignancies. This malignancy in pregnant women occurs in one per 1000 deliveries. We report a case... (Review)
Review
Osteosarcoma of the jaw represents less than 1% of all head and neck malignancies. This malignancy in pregnant women occurs in one per 1000 deliveries. We report a case of a 29-year-old woman, in the 33rd week of gestation, who presented with an expansive tumor destroying the maxillary alveolar bone, histologically composed of pleomorphic, round, spindle, or epithelioid cells and osteoid/chondroid matrix. Upon final diagnosis of osteosarcoma, the lesion was excised. To the best of our knowledge, only 10 cases of jaw osteosarcoma in pregnant women have been reported to date in the English language literature. The use of ancillary examinations, malignancy diagnosis, and cancer treatment can be challenging during pregnancy. Knowledge about jaw osteosarcoma in pregnancy can increase healthcare providers' awareness, avoid delays and misdiagnosis and potentially improve maternal and neonatal outcomes.
PubMed: 35252051
DOI: 10.4322/acr.2021.359 -
International Journal of Medical... 2022Osteosarcoma is a malignant bone tumor characterized by the direct production of osteoid tissue from tumor cells. Extracellular vesicles are membranous vesicles released... (Review)
Review
Osteosarcoma is a malignant bone tumor characterized by the direct production of osteoid tissue from tumor cells. Extracellular vesicles are membranous vesicles released by cells into the extracellular matrix, which exist widely in various body fluids and cell supernatants, and stably carry some important signaling molecules. They are involved in cell communication, cell migration, angiogenesis and tumor cell growth. Increasing evidence has shown that extracellular vesicles play a significant role in osteosarcoma development, progression, and metastatic process, indicating that extracellular vesicles can be use as biomarker vehicles in the diagnosis and prognosis of osteosarcoma. This review discusses the basic biological characteristics of extracellular vesicles and focuses on their application in osteosarcoma.
Topics: Bone Neoplasms; Cell Communication; Cell Movement; Extracellular Vesicles; Humans; Osteosarcoma
PubMed: 35928720
DOI: 10.7150/ijms.74137 -
Journal of Dental Research Jul 2022The roles of Wnt/β-catenin signaling in regulating the morphology and microstructure of craniomaxillofacial (CMF) bones was explored using mice carrying a...
The roles of Wnt/β-catenin signaling in regulating the morphology and microstructure of craniomaxillofacial (CMF) bones was explored using mice carrying a constitutively active form of β-catenin in activating Dmp1-expressing cells (e.g., daβcat mice). By postnatal day 24, daβcat mice exhibited midfacial truncations coupled with maxillary and mandibular hyperostosis that progressively worsened with age. Mechanistic insights into the basis for the hyperostotic facial phenotype were gained through molecular and cellular analyses, which revealed that constitutively activated β-catenin in Dmp1-expressing cells resulted in an increase in osteoblast number and an increased rate of mineral apposition. An increase in osteoblasts was accompanied by an increase in osteocytes, but they failed to mature. The resulting CMF bone matrix also had an abundance of osteoid, and in locations where compact lamellar bone typically forms, it was replaced by porous, woven bone. The hyperostotic facial phenotype was progressive. These findings identify for the first time a ligand-independent positive feedback loop whereby unrestrained Wnt/β-catenin signaling results in a CMF phenotype of progressive hyperostosis combined with architecturally abnormal, poorly mineralized matrix that is reminiscent of craniotubular disorders in humans.
Topics: Animals; Hyperostosis; Mice; Osteoblasts; Osteocytes; Wnt Signaling Pathway; beta Catenin
PubMed: 35114849
DOI: 10.1177/00220345211067705 -
Diagnostics (Basel, Switzerland) Jun 2023Benign tumours comprise the majority of primary vertebral tumours, and these are often found incidentally on imaging. Nonetheless, accurate diagnosis of these benign... (Review)
Review
Benign tumours comprise the majority of primary vertebral tumours, and these are often found incidentally on imaging. Nonetheless, accurate diagnosis of these benign lesions is crucial, in order to avoid misdiagnosis as more ominous malignant lesions or infection. Furthermore, some of these tumours, despite their benign nature, can have localised effects on the spine including neural compromise, or can be locally aggressive, thus necessitating active management. Haemangiomas and osteomas (enostosis) are the commonest benign tumours encountered. Others include osteoid osteoma, osteoblastoma, fibrous dysplasia, osteochondroma, chondroblastoma, haemangioma, simple bone cysts, aneurysmal bone cysts, giant cell tumours, eosinophilic granuloma and notochordal rests. The majority of lesions are asymptomatic; however, locally aggressive lesions (such as aneurysmal bone cysts or giant cell tumours) can present with nonspecific symptoms, such as back pain, neurological deficits and spinal instability, which may be indistinguishable from more commonly encountered mechanical back pain or malignant lesions including metastases. Hence, imaging, including radiography, computed tomography (CT) and magnetic resonance imaging (MRI), plays a critical role in diagnosis. Generally, most incidental or asymptomatic regions are conservatively managed or may not require any follow-up, while symptomatic or locally aggressive lesions warrant active interventions, which include surgical resection or percutaneous treatment techniques. Due to advances in interventional radiology techniques in recent years, percutaneous minimally invasive techniques such as radiofrequency ablation, sclerotherapy and cryoablation have played an increasing role in the management of these tumours with favourable outcomes. The different types of primary benign vertebral tumours will be discussed in this article with an emphasis on pertinent imaging features.
PubMed: 37370901
DOI: 10.3390/diagnostics13122006 -
Journal of Clinical Medicine Dec 2021Osteoblastoma (OB) and osteoid osteoma (OO) are benign bone-forming tumors, with nearly identical basic microscopic features. The main difference is dimension (OO has... (Review)
Review
Osteoblastoma (OB) and osteoid osteoma (OO) are benign bone-forming tumors, with nearly identical basic microscopic features. The main difference is dimension (OO has usually a nidus measuring <2 cm in diameter). In addition, OB is biologically more active than OO, with a tendency to grow in size. Historically, treatments have included surgical resection and analgesics, although invasiveness and poor tolerance have led to the current standard of care moving toward interventional radiology, where radiofrequency ablation (RFA) represents the most diffuse technique. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has recently emerged as another innovative alternative treatment, providing tumor ablation through a needleless and ionizing radiation-free modality. In addition, this technique has the ability to guarantee a very precise and controlled increase in temperature, delivering small amounts of energy that can accurately destroy only the lesion, avoiding healthy surrounding tissues. The present review focuses on MRgFUS as the less invasive, safe, effective, and durable treatment option for the management of osteoid osteoma and osteoblastoma, including a description of technical details, indications and outcomes.
PubMed: 35011867
DOI: 10.3390/jcm11010128