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Introduction Paget’s disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget’s disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. Methods Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. Results and conclusion Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

The gilthead seabream, one of the most important species in Mediterranean aquaculture, with an increasing status of exploitation in terms of production volume and aquafarming technologies, has become an important research topic over the years. The accumulation of knowledge from several studies conducted during recent decades on their functional and biological characteristics has significantly improved their aquacultural aspects, namely their reproductive success, survival, and growth. Despite the remarkable progress in the aquaculture industry, hatchery conditions are still far from ideal, resulting in frequent abnormalities at the beginning of intensive culture, entailing significant economic losses. Those deformities are induced during the embryonic and post-embryonic periods of life, and their development is still poorly understood. In the present review, we created a comprehensive synthesis that covers the various aspects of skeletal morphogenesis and anomalies in the gilthead seabream, highlighting the genetic, environmental, and nutritional factors contributing to bone deformities and emphasized the potential of the gilthead seabream as a model organism for understanding bone morphogenesis in both aquaculture and translational biological research. This review article addresses the existing lack in the literature regarding gilthead seabream bone deformities, as there are currently no comprehensive reviews on this subject.

X-linked hypophosphatemic rickets (XLH) and m.3243A>G mitochondrial disease share several clinical findings, including short stature, hearing impairment (HI), nephropathy, and hypertension. Here, we report on a case with the rare coincidence of these two genetic conditions. In early childhood, the patient presented with hypophosphatemia and bone deformities and was clinically diagnosed with XLH. This was genetically verified in adulthood with the identification of a de novo pathogenic deletion in phosphate-regulating endopeptidase homolog X-linked (PHEX). In addition, the patient developed HI and hypertension and when his mother was diagnosed with m.3243A>G, subsequent genetic testing confirmed the patient to carry the same variant. Over the next two decades, the patient developed progressive renal impairment however without nephrocalcinosis known to associate with XLH which could indicate an m.3243A>G-related kidney disease. Parallel with the progression of renal impairment, the patient developed hyperphosphatemia and secondary hyperparathyroidism. In conclusion, this case represents a complex clinical phenotype with the reversal of hypo- to hyperphosphatemia in XLH potentially mediated by the development of an m.3243A>G-associated nephropathy.

Background X-linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading tohypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH. Results The RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 3 months to 8 years and 2 months of age at the time of diagnosis (median age of 2.0 years), and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was − 1.89 ± 0.19 SDS and 55% (22/40) of patients had height SDS below—2. All cases had hypophosphatemia, serum phosphate being − 2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype—phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n = 26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis. Conclusions This study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.

Doxorubicin is a widely used chemotherapeutic drug known to induce bone loss. The mechanism behind doxorubicin-mediated bone loss is unclear, but oxidative stress has been suggested as a potential cause. Antioxidants that can counteract the toxic effect of doxorubicin on the bone would be helpful for the prevention of secondary osteoporosis. We used resveratrol, a natural antioxidant, and MitoTEMPO, a mitochondria-targeted antioxidant, to counteract doxorubicin-induced bone loss and mineralization on Sparus aurata larvae. Doxorubicin supplemented Microdiets increased bone deformities, decreased mineralization, and lipid peroxidation, whereas Resveratrol and MitoTEMPO supplemented microdiets improved mineralization, decreased bone deformities, and reversed the effects of doxorubicin in vivo and in vitro, using osteoblastic VSa13 cells. Partial Least-Squares Discriminant Analysis highlighted differences between groups on the distribution of skeletal anomalies and mineralization of skeleton elements. Calcium and Phosphorus content was negatively affected in the doxorubicin supplemented group. Doxorubicin reduced the mRNA expression of antioxidant genes, including catalase, glutathione peroxidase 1, superoxide dismutase 1, and hsp90 suggesting that ROS are central for Doxorubicin-induced bone loss. The mRNA expression of antioxidant genes was significantly increased on resveratrol alone or combined treatment. The length of intestinal villi was increased in response to antioxidants and reduced on doxorubicin. Antioxidant supplements effectively prevent bone deformities and mineralization defects, increase antioxidant response and reverse doxorubicin-induced effects on bone anomalies, mineralization, and oxidative stress. A combined treatment of doxorubicin and antioxidants was beneficial in fish larvae and showed the potential for use in preventing Doxorubicin-induced bone impairment.

Background Polygenic mutations play a significant role in the etiology of various growth-related disorders and bone deformities, influencing multiple physiological processes. Understanding the impact of polygenic mutations is crucial for the diagnosis, genetic counseling, and management of these complex conditions. Case presentation A boy first evaluated at 9 years and 10 months for short stature was diagnosed with compound heterozygous mutations in PLEC , CD96 , and RNU4ATAC genes, with comorbid congenital multiple epiphyseal dysplasia and growth hormone deficiency. These mutations collectively contributed to severe short stature, skeletal deformities, and delayed neurodevelopment. Orthopedic surgeries were performed at 9 years and 10 months (first intervention), 11 years and 6 months (second intervention), and 12 years and 9 months (third intervention), while growth hormone therapy (GHT) was initiated at 11 years and 10 months. Over 25 months of GHT, his height increased by 18 cm, bone age advanced by five years, and gait improved. Final clinical evaluation at 13 years and 11 months confirmed sustained improvements in height (137 cm) and motor function. Conclusion This case involves a child with short stature caused by rare mutations of PLEC , CD96 , and RNU4ATAC . This is the first case report documenting the concurrent presence of all three rare mutations. Orthopedic surgery and GHT were employed to improve the patient’s development and quality of life. We propose that early identification of high-risk factors, genetic screening, and comprehensive treatment can enhance therapeutic effectiveness and improve the patient’s quality of life.

Background Multiplanar external fixation systems that employ software-assisted deformity correction consist of rings connected by angled struts, defined as hexapod ring fixators (HRF). Costs and outcomes associated with the application of HRFs are not well documented. This study was designed to provide a nationwide baseline understanding of the clinical presentation, risks, outcomes and payer costs, and healthcare resource utilization (HCU) of patients requiring application of an HRF, from the day of, and up to 2 years, post-application. Methods Patients with HRF application (“index”) between 2007 and 2019 within the IBM Marketscan® Commercial Claims database were identified and categorized based on diagnosis: acquired deformity, arthropathy, congenital deformity, deep infection, nonunion, fracture, and other post-operative fracture sequelae. Demographics, comorbidities at index, complications post-index, HCU, and payments were analyzed. Payments were estimated using a generalized linear model and were adjusted for inflation to the 2020 consumer price index. Rates of deep infection and amputation were estimated up to 2 years post-index using Poisson regressions, and risk factors for each were estimated using logistic regression models. Results Six hundred ninety-five patients were included in our study (including 219 fractures, 168 congenital deformities, 68 deep infections, 103 acquired deformities). Comorbidities at index were significantly different across groups: less than 2% pediatrics vs 18% adults had 3 or more comorbidities, < 1% pediatric vs 29% adults had diabetes. Index payments ranged from $39,250–$75,350, with 12-months post-index payments ranging from $14,350 to $43,108. The duration of the HRF application ranged from 96 days to 174 days. Amputation was observed in patients with deep infection (8.9, 95% confidence interval (CI): 3.2–23.9%), nonunion (5.0, 95%CI: 1.6–15.4%) or fracture (2.7, 95%CI: 0.9–7.6%) at index. Complicated diabetes was the main predictor for deep infection (odds ratio (OR): 5.14, 95%CI: 2.50–10.54) and amputation (OR: 5.26, 95%CI: 1.79–15.51). Conclusions Findings from this longitudinal analysis demonstrate the significant heterogeneity in patients treated with HRF, and the wide range in treatment intensity, payments, and outcomes. Risks for deep infection and amputation were primarily linked to the presence of complicated diabetes at the time of HRF application, suggesting a need for careful management of comorbid chronic conditions in patients requiring HRF for orthopedic care.

Abstract Purpose Several hexapod external fixators are used in the treatment of bone fracture and deformity corrections. One characteristic of all of them is the requirement for manual adjustment of the fixator struts. The purpose of this study was to introduce a novel robotic system that executes automatic adjustment of the struts. Methods Ten patients were treated for various bone deformities using a hexapod external fixator with the Auto Strut system. This new system automatically adjusts the fixator struts according to a hexapod computer-assisted correction plan. During each visit, the progress of the correction was assessed (clinically and radiographically) and reading of the strut scale numbers was performed and compared with the original treatment plan. Results All patients completed treatment during the follow-up period, achieving all planned correction goals, except from one patient who switched to manual struts due to personal preference. The device alarm system was activated once with no device-related adverse events. Duration of distraction ranged between ten and 90 days with a distraction index ranging between eight and 15 days/cm. Regenerate consolidation time between one and seven months. In total, 48 struts of eight patients were recorded and analyzed. In all, 94% of the final strut number readings presented a discrepancy of 0 mm to 1 mm between planned and actual readings, indicating high precision of the automatic adjustment. Conclusion This study presents preliminary results, showing that Auto Strut can successfully replace the manual strut adjustment providing important advantages that benefit the patient, the caregiver and the surgeon. Level of Evidence Level II