Explore the vast range of titles available.

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin’s protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE −/− mice and hSOST ki .ApoE −/− mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOST ki mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation. Antibodies targeting sclerostin can ameliorate postmenopausal osteoporosis but present some cardiovascular risk. Here the authors show that the cardiovascular and skeletal effects of sclerostin are mediated by different loops, suggesting ways to preserve the positive effects on bone formation while avoiding the negative cardiovascular consequences.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months–90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ − 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Osteogenesis imperfecta (OI) is a connective tissue disorder affecting the skeleton and other organs, which has multiple genetic patterns, numerous causative genes, and complex pathogenic mechanisms. The previous classifications lack structure and scientific basis and have poor applicability. In this paper, we summarize and sort out the pathogenic mechanisms of OI, and analyze the molecular pathogenic mechanisms of OI from the perspectives of type I collagen defects(synthesis defects, processing defects, post-translational modification defects, folding and cross-linking defects), bone mineralization disorders, osteoblast differentiation and functional defects respectively, and also generalize several new untyped OI-causing genes and their pathogenic mechanisms, intending to provide the evidence of classification and a scientific basis for the precise diagnosis and treatment of OI.

Background Thyroid hormone is a known pivotal factor that affects bone metabolism; however, whether bone microarchitecture is associated with thyroid hormone sensitivity is poorly understood. The trabecular bone score (TBS) serves as an essential indicator for assessing bone microarchitecture. This study aimed to investigate the relationship between sensitivity to thyroid hormones and TBS in euthyroid individuals. Methods This cross-sectional study involved 3320 euthyroid participants from the National Health and Nutrition Examination Survey (NHANES) 2007–2008. Data, including thyroid function, TBS and other related parameters, were extracted and analyzed. The indices of thyroid hormone sensitivity, including the thyrotropin thyroxine resistance index (TT4RI), thyroid-stimulating hormone index (TSHI), thyroid feedback quantile-based index (TFQI) and parametric thyroid feedback quantile-based index (PTFQI), were calculated. Greater values of these indicators indicated a greater degree of impaired thyroid hormone sensitivity. Results Impaired sensitivity to thyroid hormones was associated with degraded bone microarchitecture following adjustments for confounding variables (TT4RI: P  = 0.005, TSHI: P  = 0.008, TFQI: P  = 0.003 and PTFQI: P  = 0.006). The restricted cubic spline model demonstrated a positive relationship between TT4RI, TSHI, TFQI, PTFQI and degraded bone microarchitecture. Similar findings were observed in the analysis of subgroups stratified by age, sex, race, diabetes status, hypertension status and hyperuricemia status. Conclusions In euthyroid individuals, impaired sensitivity to thyroid hormones is associated with degraded bone microarchitecture. However, further studies are required to confirm this relationship.

Background Due to its occult position, complex anatomical structure, and spatial relationships, the causative tumor of Tumor-Induced Osteomalacia (TIO) in the hip region is quite difficult to detect and qualitatively diagnose in clinical practice. In this regard, clinicians often lack sufficient knowledge about such tumors, leading to frequent missed diagnoses, misdiagnoses, and unreasonable treatment. Objective This study aimed to investigate the clinical characteristics of TIO patients with culprit soft tissue tumors in the hip region and evaluate the effect of surgical treatment on these individuals to improve clinicians’ understanding of the rare phenomenon. Methods The clinical data of all patients, from January 2013 to January 2023, who underwent surgical treatment for hip located culprit soft tissue tumors by the subspecialty group on bone and soft tissue tumors at our institution, were retrospectively analysed. Specifically, the clinical characteristics and therapeutic effects were examined and the patients’ clinical experience was summarized. Results Twenty-two patients, who met the inclusion criteria, were included. All patients experienced varying degrees of bone pain, commonly accompanied by weakness (16/22) and limited mobility (21/22), and 10 patients (45.5%) experienced a significant reduction in body height during the course of the disease. All patients underwent orthopedic surgery in the hip region, as hypophosphatemia occurred in all of them. Pathological diagnosis was confirmed to be consistent with causative tumors of TIO. All patients experienced a gradual increase in serum phosphorus postoperatively during short-term follow-up. The follow-up period was between 1 and 10 years, and the postoperative serum phosphorus levels were monitored at our hospital or other facilities close to the patients. Conclusions Oncogenic soft tissue tumors for TIO in the hip region are occult, making clinical misdiagnoses or missed diagnoses highly likely. Therefore, enhancing the clinician’s understanding of this rare condition is imperative. Notably, for TIO patient whose culprit tumor can be located, complete surgical resection of the causative tumor is the best treatment option. Furthermore, close postoperative monitoring of serum phosphorus is necessary, and patients should be subjected to long-term follow-up for prompt detection of recurrent conditions. Highlights Tumor-induced osteomalacia caused by causative soft tissue tumor in the hip region is a rare entity, resulting in great challenges to orthopedists. Qualitative and localized diagnosis led by multi-disciplinary team is a prerequisite for subsequent surgical intervention. For the inguinally located culprit tumors, it may be quite effective after remove the culprit tumor directly and surgical resection may bring huge benefit. Exploring the site of onset of the causative tumor is beneficial for improving the treatment strategy of orthopedic surgery and understanding the prognostic characteristics of TIO patients.

Background Current research on osteoporosis (OP) in hemophilia is insufficient. The suitability of high-resolution peripheral quantitative computed tomography (HR-pQCT) for evaluating osteoporosis in hemophilia remains unclear. Aim To investigate the current status of osteoporosis and the applicability of HR-pQCT in adult hemophilia patients. Methods Thirty three hemophilia patients aged 23–49 years were recruited. X-ray examinations were performed on the bleeding joints. Dual energy X-ray absorptiometry (DXA) and HR-pQCT were used to assess bone mineral density (BMD). The HR-pQCT values of the distal tibia and radius were compared between hemophilia patients and healthy controls(HCs). Results All bleeding joints showed local osteoporosis on X-ray. Only 33.3% of patients had a hip BMD lower than the expected value according to DXA. The Tb.vBMD(98.5 ± 44.2 mg/cm 3 ), Tt.Ar(612.5 ± 163.5mm 2 ),Tb.Ar(487.0 ± 175.6mm 2 ), Ct.Ar(117.0 ± 25.7mm 2 ), Tb.BV/TV(0.2 ± 0.1), Tb.N(0.9 ± 0.3 1/mm), Ct.Pm(96.3 ± 13.8 mm) of the distal tibia and Tt.Ar(248.4 ± 53.1mm 2 ),Tb.Ar(186.0 ± 55.1mm 2 ), Ct.Ar(66.1 ± 14.4 mm 2 ), Ct.Pm(68.1 ± 7.1 mm) of the distal radius in the hemophilia group was significantly lower than the HCs(tibia Tb.vBMD:186.4 ± 44.3mg/cm 3 , Tt.Ar:906.8 ± 135.0mm 2 ,Tb.Ar:743.7 ± 137.6mm 2 , Ct.Ar:169.3 ± 21.9mm 2 ,Tb.BV/TV:0.3 ± 0.1, Tb.N:1.5 ± 0.2 1/mm,Ct.Pm:117.8 ± 8.2 mm; radius Tt.Ar:285.7 ± 35.6 mm 2 , Tb.Ar:83.8 ± 7.9mm 2 , Ct.Ar:0.3 ± 0.1mm 2 , Ct.Pm:80.2 ± 4.3 mm) with statistically significant differences ( p  < 0.05). Correlation analysis showed a positive correlation ( r  = 0.768, p  = 0.016) between femoral neck BMD with DXA and total volumetric BMD(Tt.vBMD) at the distal tibia. Conclusion The bone health status of adult hemophilia patients in China is worrying. The occurrence of OP may be accompanied by varying degrees of bone loss, bone destruction, and structural abnormalities observed in both trabecular and cortical bones of the upper and lower limbs. The condition of the trabecular bones in the lower limbs is particularly severe. The correlation between BMD measurements obtained from HR-pQCT and DXA is strong.

Arguments regarding the biocompatibility of graphene-based materials (GBMs) have never ceased. Particularly, the genotoxicity (e.g., DNA damage) of GBMs has been considered the greatest risk to healthy cells. Detailed genotoxicity studies of GBMs are necessary and essential. Herein, we present our recent studies on the genotoxicity of most widely used GBMs such as graphene oxide (GO) and the chemically reduced graphene oxide (RGO) toward human retinal pigment epithelium (RPE) cells. The genotoxicity of GO and RGOs against ARPE-19 (a typical RPE cell line) cells was investigated using the alkaline comet assay, the expression level of phosphorylated p53 determined via Western blots, and the release level of reactive oxygen species (ROS). Our results suggested that both GO and RGOs induced ROS-dependent DNA damage. However, the DNA damage was enhanced following the reduction of the saturated C–O bonds in GO, suggesting that surface oxygen-containing groups played essential roles in the reduced genotoxicity of graphene and had the potential possibility to reduce the toxicity of GBMs via chemical modification.

Objective Hypophosphatasia (HPP) is a rare inherited disorder caused by ALPL gene mutations, with fracture nonunion being a serious complication. This study investigated the effects of teriparatide and asfotase alfa (AA) on femoral fracture healing of an adult patient with HPP, accompanied with a literature review. Methods A 37-year-old woman wheelchair-bound was diagnosed with HPP due to an extremely low serum alkaline phosphatase (ALP) level (4–10 U/L), who suffered from bilateral femur pain and non-union of femoral shaft fractures on both sides. Compound heterozygous missense mutations (c.382G > A and c.461C > T) were identified in exon5 of ALPL gene. The patient received teriparatide sequential AA therapy. Serum levels of ALP, β-isomerized carboxy-telopeptide of type I collagen (β-CTX) and procollagen type 1 amino-terminal peptide (P1NP), bone mineral density (BMD) and skeletal X-ray were measured during the treatment. Literature was searched by keywords of “Hypophosphatasia”, “HPP”, “ALPL”, “TNSALP”, “ALP” combined with “Asfotase alfa”, “AA”, “enzyme replacement therapy”, and “ERT”. Results After unsuccessful 6-month teriparatide treatment for femoral fracture, AA treatment was initiated, at a dose of 2 mg/kg, 3 times a week. After the first month of AA treatment, serum ALP level increased from 4 to 9206 U/L, and serum calcium and phosphate levels decreased, with increase in PTH, β-CTX, and P1NP levels. After 4 months of AA treatment, her bone pain significantly alleviated, accompanied by significant shortening of the fracture line. After 10 months of AA therapy, the fracture demonstrated complete healing and the patient could walk independently. BMD at lumbar spine and hips was significantly increased. Among 295 adult patients with HPP reported in the literature, 213 (72.2%) exhibited skeletal-related symptoms and 91 (30.8%) presented with bone fractures. In addition to skeletal manifestations, the patients presented with early tooth loss, muscle weakness and ectopic calcification. AA treatment, spanning 9 weeks to 3 years, has been shown to increase ALP levels, promote fracture healing, improve mobility, and alleviate bone pain. Conclusion Adult HPP patients mainly present with recurrent or poorly healing fractures, bone pain, and early loss of teeth. AA replacement therapy can effectively promote fracture healing, relieve bone pain, and enhance mobility.

Mutations in the gene LMNA cause a wide spectrum of diseases that are now referred to laminopathies, such as muscular dystrophies, cardiomyopathies, and progeroid syndromes. Atypical progeroid syndrome (APS) is a type of progeroid syndrome mainly associated with LMNA mutations. Abnormal skeletal features associated with APS, such as osteoporosis and acroosteolysis, are rarely reported, and recurrent fractures have never been documented. We present a 16-year-old Chinese male patient with the typical features of APS, such as progeroid manifestations, cutaneous mottled hyperpigmentation, generalized lipodystrophy, and severe metabolic complications. The patient has also been detected with some rare and severe skeletal features, such as severe osteoporosis, generalized thinning of cortical bone, and recurrent femoral fractures. Genetic mutation detection in the LMNA gene revealed a de novo heterozygous mutation, the c. 29C>T (p. T10I).

Paget’s disease of bone (PDB) is a rare metabolic bone disorder, which is extremely rare in Asian population. This study aimed to investigate the phenotypes and the pathogenic mutations of woman with early-onset PDB. The clinical features, bone mineral density, x-ray, radionuclide bone scan, and serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and β-carboxy-terminal cross-linked telopeptide of type 1 collagen (β-CTX) were measured in detail. The pathogenic mutations were identified by whole-exon sequencing and confirmed by Sanger sequencing. We also evaluated the effects of intravenous infusion of zoledronic acid on the bones of the patient and summarized the phenotypic characteristics of reported patients with mutation at position 155 of the valosin-containing protein (VCP). The patient only exhibited bone pain as the initial manifestation with vertebral compression fracture and extremely elevated ALP, P1NP, and β-CTX levels; she had no inclusion body myopathy and frontotemporal dementia. The missense mutation in exon 5 of the VCP gene (p.Arg155His) was identified by whole-exome sequencing and further confirmed by Sanger sequencing. No mutation in candidate genes of PDB, such as SQSTM1, CSF1, TM7SF4, OPTN, PFN1, and TNFRSF11A, were identified in the patient by Sanger sequencing. Rapid relief of bone pain and a marked decline in ALP, P1NP, and β-CTX levels were observed after zoledronic acid treatment. Previously reported patients with VCP missense mutation at position 155 (R155H) always had myopathy, frontotemporal dementia, and PDB, but the patient in this study exhibited only PDB. This was the first report of R155H mutation-induced early-onset in the VCP gene in Asian population. PDB was the only manifestation having a favorable response to zoledronic acid treatment. We broadened the genetic and clinical phenotype spectra of the VCP mutation.