Search Results (396)

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Background: Uterine fibroids (UFs) and endometriosis are gynecological conditions that significantly increase morbidity among women of reproductive age. Relugolix, a novel gonadotropin-releasing hormone receptor antagonist, is approved in combined therapy for the management of symptoms related to these disorders. However, its potential impact on bone mineral density (BMD) and osteoporosis risk should be considered when using a gonadotropin-releasing hormone (GnRH) antagonist. This systematic review aims to evaluate the effects of daily relugolix intake in monotherapy and combination therapy on BMD, ensuring safe long-term management. Methods: A systematic literature review was conducted following PRISMA 2020 guidelines. Searches were performed in PubMed, Medline, and the Cochrane Library. Relevant clinical guidelines from international societies were also reviewed. Studies assessing the impact of relugolix on BMD were selected, and data on treatment efficacy, adverse effects, and bone health outcomes were synthesized. Results: Relugolix monotherapy has been associated with significant BMD loss due to its potent estrogen-suppressing effect. To mitigate this, combination therapy with estradiol and norethisterone acetate has been developed. Although initial monotherapy before transitioning to combination therapy results in transient BMD reduction, clinical trials have demonstrated that relugolix combination therapy maintains BMD over two years while effectively reducing endometriosis- and UF-related symptoms. Conclusions: Relugolix combination therapy is an effective and well-tolerated treatment for UFs and endometriosis, minimizing the risk of hypoestrogenism-related bone loss while maintaining clinical benefits. Although monotherapy may lead to transient BMD reduction, combination therapy appears to stabilize bone health. Full article

Xylosyltransferase-I (XT-I) plays a crucial role in skeletal development and cartilage integrity. An XT-I deficiency is linked to severe bone disorders, such as Desbuquois dysplasia type 2. While animal models have provided insights into XT-I’s role during skeletal development, its specific effects on adult bone homeostasis, particularly in human mesenchymal stem cell (hMSC) differentiation, remain unclear. This study investigates how XT-I deficiency impacts the differentiation of hMSCs into chondrocytes, osteoblasts, and adipocytes—key processes in bone formation and repair. The aim of this study was to elucidate for the first time the molecular mechanisms by which XT-I deficiency leads to impaired bone homeostasis. Using CRISPR-Cas9-mediated gene editing, we generated XYLT1 knockdown (KD) hMSCs to assess their differentiation potential. Our findings revealed significant disruption in the chondrogenic differentiation in KD hMSCs, characterized by the altered expression of regulatory factors and extracellular matrix components, suggesting premature chondrocyte hypertrophy. Despite the presence of perilipin-coated lipid droplets in the adipogenic pathway, the overall leptin mRNA and protein expression was reduced in KD hMSCs, indicating a compromised lipid metabolism. Conversely, osteogenic differentiation was largely unaffected, with KD and wild-type hMSCs exhibiting comparable mineralization processes, indicating that critical aspects of osteogenesis were preserved despite the XYLT1 deficiency. In summary, these results underscore XT-I’s pivotal role in regulating differentiation pathways within the bone marrow niche, influencing cellular functions critical for skeletal health. A deeper insight into bone biology may pave the way for the development of innovative therapeutic approaches to improve bone health and treat skeletal disorders. Full article

Background/Objectives: Cystic fibrosis (CF) is a multi-system disorder characterized by chronic respiratory failure, malnutrition, and impaired growth. Achieving linear growth above the 50th percentile is associated with better pulmonary outcomes. Since October 2022, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been approved in Italy for children aged ≥6 years. However, data on its impact on height velocity (HV) remain lacking. This study aims to evaluate growth patterns by HV and explore differences according to the CFTR variant genotype. Methods: We conducted a prospective single-center study at the CF Unit of Bambino Gesù Children’s Hospital involving 24 children aged 6–11 years eligible for ETI treatment. Baseline assessments included height, weight, body mass index (BMI), bone mineral density (BMD), body composition (via bioelectrical impedance analysis, BIA), and muscle strength (one-minute sit-to-stand test (1STST)). Height, weight, HV, and BMI standard deviation scores (SDS) were calculated for the 6 months before and after ETI initiation. Results: The mean age of the cohort was 8.7 ± 1.9 years (F/M: 12/12), with most patients naïve to CFTR modulators. A significant increase in HV was observed post-ETI: from 4.2 ± 2.0 cm/year (−1.96 ± 2.4 SDS) in the 6 months before treatment to 7.1 ± 3.0 cm/year (+1.5 ± 3.7 SDS) after treatment initiation (p < 0.0001). Patients with F508del/minimal function (F/MF) genotypes (n = 11) showed significantly greater HV compared to those with F508del/F508del (F/F, n = 5) and F508del/residual function (F/RF, n = 8) genotypes (p < 0.0001). No significant differences were observed among genetic groups in baseline BMD or lean mass. Conclusions: ETI treatment significantly and rapidly improves HV in children with CF, particularly in those with F/MF genotypes. These findings underscore the role of CFTR modulator therapy in promoting linear growth, a key indicator of health in pediatric CF populations. Full article

Background: Female collegiate runners may be at high risk for disordered eating and poor bone health, which are characteristics of the female athlete triad. Intuitive eating can promote healthy eating behavior and adequate calorie intake, central variables in calculating energy availability, an underlying cause of low bone mass in athletes. Poor bone health can contribute to injury, preventing optimal performance for athletes. The purpose of this study was to assess intuitive eating, energy availability, and bone mineral density in female college runners with comparison to non-athletes. Methods: Female college athletes (n = 13, 19.5 ± 1.4 yrs) and non-athletes (n = 12, 19.9 ± 1.3 yrs) completed the Intuitive Eating Scale, Eating Disorder Examination Questionnaire, and menstrual history survey. Bone mineral density and body composition were measured using a dual-energy X-ray absorptiometer (DEXA). A 3-day diet record and exercise log were used to assess dietary intake, estimate energy expenditure, and calculate energy availability. Results: Intuitive eating was inversely correlated with disordered eating (r = −0.596, p = 0.002). Intuitive eating scores were not correlated to calorie intake, energy availability, bone mass, or percent body fat. Runners consumed significantly more calories, calcium, magnesium, phosphorus, and protein (g/kg) than non-athletes. Energy availability and bone mineral density were not significantly different between runners and non-athletes. Conclusions: Intuitive eating is associated with healthy eating behaviors in college-age females and was not related to energy availability, bone density, or body composition in this population. Future research could explore the use of intuitive eating principles in reducing disordered eating and addressing low energy availability in female runners and non-athletes. Full article

Background/Objectives: Secondary hyperparathyroidism (SHPT) is a prevalent complication in end-stage renal disease, often necessitating surgical intervention when refractory to medical therapy. The optimal surgical strategy—subtotal parathyroidectomy (SPTX) versus total parathyroidectomy with/without autotransplantation (TPTX ± AT)—remains debated, especially considering postoperative complications like persistent HPT and hungry bone syndrome (HBS). This study aimed to compare early surgical outcomes and identify predictors for postoperative complications in patients undergoing SPTX and TPTX + AT. Methods: We conducted a retrospective, single-center observational study involving 93 dialysis patients who underwent PTX for drug-refractory SHPT. Patients were analyzed according to surgical procedure (SPTX vs. TPTX + AT), focusing on postoperative complications such as cervical bleeding, reintervention rates, and the incidence of HBS. Multivariate logistic regression was utilized to identify predictors of these outcomes. Results: TPTX + AT demonstrated superior control of HPT, with significantly lower rates of reintervention compared to SPTX (7.1% vs. 23.5%, p = 0.037). However, TPTX + AT was associated with a higher incidence of HBS (57.1% vs. 35.3%, p = 0.039). Independent predictors of reintervention included absence of concomitant thymectomy, preoperative hypercalcemia, fewer visualized glands preoperatively, and preoperative PTH > 2000 pg/mL. Elevated alkaline phosphatase levels (>300 U/L), severe bone pain, and the TPTX procedure itself were significant predictors of HBS. Conclusions: Surgical strategy for SHPT should be individualized, balancing the lower recurrence risk associated with TPTX + AT against its higher likelihood of postoperative hypocalcemia. Preoperative biochemical markers and clinical features could potentially influence operative decision-making and optimize patient outcomes. Full article

Background: Chronic kidney disease (CKD) is an established global health problem, with the increased prevalence of vascular inflammation, accelerated atherogenesis, and thrombotic risk all contributing to overall cardiovascular risk. The major CKD-specific risk factor is presumed to be the accumulation of uremic toxins in circulation and tissues, further accelerating the progression of CKD and its co-morbidities, including those of bone mineral disorders and cardiovascular diseases. Materials and Methods: In our narrative review, we focused on non-traditional cardiovascular risk factors, as they evolve with declined kidney function and are potentially further modulated by the choice of kidney replacement therapy. Results: Based on the data from the literature to date, the pre-eminent role of non-traditional risk factors emerges to mediate inflammation and increased cardiovascular mortality. In particular, patients receiving hemodialysis (HD) display dramatically increased CVD-mediated mortality. This intensified state of inflammation may be linked to the direct exposure of the bloodstream to a bio-incompatible environment in HD; for both complement-mediated and non-complement-mediated reactions, the possible contribution of neutrophil extracellular traps and complement activation-related pseudoallergy are reviewed in detail. Conclusions: Our narrative review emphasizes key elements of a bio-incompatible HD environment that may contribute to increased cardiovascular mortality in patients receiving HD. Summarizing these results may provide conceptual opportunities to develop new therapeutic targets. Full article

Tanshinones are a class of lipophilic diterpenoid quinones extracted from Salvia miltiorrhiza (Dan shen), a widely used herb in traditional Chinese medicine. These compounds, particularly tanshinone IIA (T-IIA) and sodium tanshinone sulfonate (STS), have been acknowledged for their broad spectrum of biological activities, including anti-inflammatory, antioxidant, anti-tumor, antiresorptive, and antimicrobial effects. Recent studies have highlighted the potential of tanshinones in the treatment of osteolytic diseases, characterized by excessive bone resorption, such as osteoporosis, rheumatoid arthritis, and periodontitis. The therapeutic effects of tanshinones in these diseases are primarily attributed to their ability to inhibit osteoclast differentiation and activity, suppress inflammatory cytokine production (e.g., tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6), and modulate critical signaling pathways, including NF-kB, MAPK, PI3K/Akt, and the RANKL/RANK/OPG axis. Additionally, tanshinones promote osteoblast differentiation and mineralization by enhancing the expression of osteogenic markers such as Runx2, ALP, and OCN. Preclinical models have demonstrated that T-IIA and STS can significantly reduce bone destruction and inflammatory cell infiltration in arthritic joints and periodontal tissues while also enhancing bone microarchitecture in osteoporotic conditions. This review aims to provide a comprehensive overview of the pharmacological actions of tanshinones in osteolytic diseases, summarizing current experimental findings, elucidating underlying molecular mechanisms, and discussing the challenges and future directions for their clinical application as novel therapeutic agents in bone-related disorders, especially periodontitis. Despite promising in vitro and in vivo findings, clinical evidence remains limited, and further investigations are necessary to validate the efficacy, safety, and pharmacokinetics of tanshinones in human populations. Full article

Fracture risk is a serious yet underrecognized complication among patients with chronic kidney disease (CKD), especially in those with stages G3-G5D. The overlap between CKD-Mineral and Bone Disorder (CKD-MBD) and osteoporosis leads to complex bone changes that increase the likelihood of fragility fractures. Studies show that 18% to 32% of CKD patients also have osteoporosis, and these individuals are more than 2.5 times as likely to suffer from fractures compared to those without CKD. In the advanced stages of the disease, fracture risk is up to four times higher than in the general population, with the femur, forearm, and humerus being the most commonly affected sites. Hip fractures are of particular concern as they are linked to longer hospital stays and higher rates of morbidity and mortality. Furthermore, dialysis patients who experience hip fractures have a mortality rate 2.4 times higher than those in the general population with similar fractures. This increased risk underscores the need for proactive bone health maintenance in CKD patients to prevent fractures and related complications. This review explores the underlying pathophysiological mechanisms, diagnostic challenges, and treatment options related to bone fragility in CKD. Diagnostic tools, such as bone mineral density (BMD) assessments, the trabecular bone score (TBS), and biochemical markers, remain underused, especially in advanced CKD stages. Recent treatment strategies emphasize a multidisciplinary, stage-specific approach, incorporating calcium and vitamin D supplements, anti-resorptive agents like denosumab, and anabolic therapies such as teriparatide and romosozumab. Effective management needs to be tailored to the patient’s bone turnover status and stage of CKD. Despite progress in understanding bone fragility in CKD, significant gaps remain in both diagnosis and treatment. Personalized care, guided by updated KDIGO recommendations and based on an interdisciplinary approach, is essential to reduce fracture risk and improve outcomes in this vulnerable population. Further research is needed to validate risk assessment tools and refine therapeutic protocols. Full article

Background and Objectives: Calcium is an essential mineral that plays a vital role in fetal development and maternal health during pregnancy. The World Health Organization recommends a daily calcium intake of 1.5–2 g for pregnant adult women. Calcium deficiency during gestation may lead to complications, such as gestational hypertension, preeclampsia, loss of bone mineral density, impaired fetal development, and other adverse pregnancy outcomes. The aim of the present review is to evaluate the current clinical evidence on calcium intake during pregnancy. Methods: The present systematic review was conducted according to the PRISMA 2020 statement by searching two major databases, PubMed and Mendeley. The study protocol was registered in the Open Science Framework (DOI: osf.io/rvj7z). Inclusion criteria were clinical trials on calcium supplementation during pregnancy. Exclusion criteria were clinical guidelines, reviews, case reports, case series, letters, and commentaries. The Newcastle–Ottawa Scale was used to assess the risk of bias in the included studies. Results: Initially, 451 publications were identified, and after removal of duplicates and screening of titles and/or abstracts and/or full texts, 34 studies were included. The number of participants ranged between 30 and 22,000 women. Calcium supplementation was associated with lower incidence of and less severe gestational hypertension and preeclampsia, lower risk of preterm birth, longer pregnancy duration and higher neonatal birth weight, and improved maternal bone mineral density postpartum. When the doses were split up into smaller doses, the benefits were strongest with high-dose regimens (1.5–2 g/day). Conclusions: Calcium supplementation during pregnancy has beneficial effects on maternal and neonatal health, especially in populations with insufficient dietary daily calcium intake and women at high risk of hypertensive disorders. Daily dose may vary according to individual needs, daily dietary calcium intake, and general health status. Further large-scale randomized controlled trials (RCTs) are necessary to confirm these findings. Full article

Osteogenesis imperfecta type VI is a rare autosomal recessive disorder characterized by bone fragility and defective mineralization, caused by pathogenic variants in the SERPINF1 gene. This study aimed to expand the understanding of OI type VI by analyzing clinical, radiological, and molecular findings in four patients from three unrelated families. Genotyping revealed two novel SERPINF1 variants, c.185G>T (p.Gly62Val) and c.992_993insCA (p.Glu331Asnfs), in a compound heterozygous state in one patient, and a known pathogenic variant, c.261_265dup (p.Leu89Argfs26), in a homozygous form in three patients. Clinical manifestations included early-onset fractures, severe skeletal deformities, impaired mobility, and growth failure. Radiological assessments revealed multilevel and multiplanar bone deformities and metaphyseal widening. RNA analysis demonstrated that the c.992_993insCA variant results in a truncated PEDF protein without triggering nonsense-mediated decay. Population screening identified a carrier frequency of 0.0044 for the c.261_265dup variant, suggesting a founder effect in the Tuvinian population. These findings expand the mutational spectrum of the SERPINF1 gene and provide new insights into the phenotypic variability of OI type VI. Our results highlight the importance of genetic screening in isolated populations and emphasize the need for further research to develop more effective therapeutic approaches for patients with limited response to bisphosphonate therapy. Full article

Bone metabolism is a dynamic process involving continuous bone formation and resorption, orchestrated by the interplay between osteoblasts and osteoclasts. Osteoporosis (Op), the most prevalent osteo-metabolic disorder globally, results from an imbalance in this remodeling cycle. Hashimoto’s thyroiditis (HT), a chronic autoimmune thyroid disorder, has been increasingly recognized as a contributor to bone loss, even in euthyroid individuals. HT is marked by immune dysregulation, autoantibody production, and chronic inflammation, factors that can alter bone remodeling. Furthermore, both thyroid-stimulating hormone (TSH) and thyroid hormones (THs) independently influence bone health. Low TSH and elevated TH levels, including in subclinical states, have been linked to reduced bone mineral density (BMD) and increased fracture risk. Nutritional factors, particularly selenium and iodine intake, modulate both thyroid and bone function, and can be considered as a link between HT and Op. In particular, antioxidant-rich diets such as the Mediterranean diet may confer protective effects. This review integrates current clinical and experimental evidence linking HT with bone metabolism disorders, emphasizing the multifactorial nature of bone fragility in autoimmune thyroid disease and the potential role of diet in mitigating its impact. Full article

Elite female tennis players are among those at high risk for developing the Female Athlete Triad (Triad), characterized by three interrelated conditions: energy deficiency/low energy availability, menstrual dysfunction, and low bone mineral density. From 1996 to 2022, the Women’s Tennis Association (WTA) developed and implemented prevention, education, and management plans for female athletes at risk for, or exhibiting symptoms of, the Triad. This article reviews the WTA Triad protocol, developed in 2018 and utilized through 2022, in collaboration with subject matter experts in the Women’s Health and Exercise Laboratory at The Pennsylvania State University. The WTA Triad protocol (1996–2022) includes prevention and management programs implemented by a multidisciplinary Performance Health Team to include screening for “red flags” during annual physicals or upon clinical presentation of a menstrual problem, bone disorder, or nutritional concern; targeted education for players, coaches, and other support team members with handouts and lectures on nutrition and body image to prevent energy deficiency; and a multidisciplinary protocol to guide treatment and return-to-play decisions. Other sport governing bodies can adopt similar multi-layered programs and practices for their athletes, coaches, and support teams to educate, screen, manage, and help to prevent the development of the Triad. Full article

It is now widely recognized that maintaining magnesium (Mg) homeostasis is critical for health, especially in the context of chronic kidney disease (CKD). Patients with CKD commonly develop hyperphosphatemia and secondary hyperparathyroidism, which are controlled by therapies targeting intestinal phosphate absorption and circulating calcium levels or by modulating parathyroid calcium sensing. Notably, Mg supplementation may provide dual benefits by promoting bone formation and maintaining normal mineralization with slightly elevated serum levels. Importantly, low Mg levels are associated with mortality risk in CKD, highlighting the importance of maintaining adequate serum Mg levels in these patients. Particularly, kidney transplant (KT) patients have lower circulating Mg levels, likely due to interactions with immunosuppressive treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown survival benefits in CKD and increased serum Mg levels, suggesting that Mg regulation may contribute to these outcomes. Overall, Mg plays a key role in CKD-associated mineral and bone disorders (CKD-MBD). Thus, understanding the mechanisms underlying the alteration of Mg homeostasis in CKD could improve clinical outcomes. This review summarizes the basic and clinical studies demonstrating (1) the key actions of Mg in CKD-MBD, including secondary hyperparathyroidism and bone abnormalities; (2) the distinctive profile of KT patients for Mg homeostasis; and (3) the interaction between commonly used drugs, such as SGLT2 inhibitors or immunosuppressive treatments, and Mg metabolism, providing a broad understanding of both the key role of Mg in the context of CKD and the treatments that should be considered to manage Mg levels in CKD patients. Full article

In patients with chronic kidney disease (CKD), cardiovascular events (CVA) are the main cause of morbidity and mortality. Vascular calcification, linked to bone mineral metabolism disorders such as elevated serum phosphate, parathyroid hormone (PTH), and FGF23, well-known uremic toxins, aggravate this risk. Calcimimetics are allosteric activators of the calcium-sensing receptor (CaSR), a G protein-coupled receptor that regulates PTH secretion and synthesis in response to changes in extracellular calcium in the parathyroid glands. Through direct and indirect mechanisms, they have demonstrated their efficacy in reducing the progression of vascular, valvular, and soft tissue calcification in experimental studies. Although clinical studies in dialysis patients did not achieve statistical significance in their primary objectives, positive results in subgroup analyses suggest that the lack of significance may be attributable to the short follow-up period. This finding highlights the need to consider early treatment strategies, especially in advanced stages of chronic kidney disease, to more effectively address the progression of vascular calcification through serum uremic toxins control. Full article