Body composition, core stability, flexibility, balance, and psychological status in female athletes with primary dysmenorrhea.

Family planning and contraception are central to disease management in people with rheumatic musculoskeletal diseases (RMD), particularly systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), in whom unplanned pregnancy can carry substantial maternal and fetal risk. This review summarizes current evidence and guideline-based recommendations regarding contraceptive choices in women with SLE and APS, with a focus on thrombotic risk, bone health, and cardiovascular considerations. Estrogen-containing hormonal contraception is well established as a pro-thrombotic risk and should be avoided in those with APS, antiphospholipid antibodies (aPL), lupus nephritis, or at least moderately active SLE. Emerging data also suggest an association of certain higher dose progestins such as norethindrone acetate, and injectable preparations such as depot medroxyprogesterone acetate (DMPA), with increased venous thromboembolism (VTE) risk. Regarding bone health, oral contraceptive pills (OCPs) and combined hormonal contraception (CHC) may slow the rate of bone mass acquisition in adolescents with uncertain long-term effects on fracture risk, whereas use in adult women is associated with modestly higher bone mineral density and lower osteoporotic risk. While awareness of the importance of contraception in the rheumatology community is improving, real-world practice reveals that implementation of reproductive health guidelines is lagging. For women with SLE and APS, contraception selection must account for thrombotic risk, bone health, and cardiovascular comorbidities. Long-acting reversible contraceptives, particularly progestin-only intrauterine devices (IUDs) and subdermal implants, remain highly effective and well tolerated for those with SLE and APS. Ongoing efforts to improve guideline implementation, shared decision-making, and patient and provider education are essential to reduce unplanned pregnancies and optimize reproductive outcomes in this population.

Therapeutic effect of mitochondrial transfer on bone tissue diseases: treatment strategy of mitochondrial transplantation and delivery technology.

Endometriosis presents a multitude of challenges for individuals. Current treatment of the disease is based on pharmacotherapy that aims to relieve pain, improves future fertility, potentially slows disease progression and lessen the likelihood of recurrence. The present review outlines recent reports on the importance of Gonadotropin-Releasing Hormone antagonists/antagonists and a new prospective as a significant second- line treatment option. A review of the literature from the last 5 years was conducted. The search included the following medical subject: "endometriosis", "GnRh agonists", "GnRh antagonists", "pharmacotherapy".The articles published in English were included. Publications without full text access and duplicates were rejected. Current researches no longer focuse exclusively on finding new GnRH agonists/antagonists, but rather on maximizing their usage, in favour of the latter ones . Multiple active substances are now being combined into one tablet, which makes it easier for patients to take their medication and improves their adherence to treatment recommendations. 24 months monotherapy of linzagolix did not indicate any clinically relevant impact on overall bone condition in comparison to placebo group. Relugolix combination therapy maintained bone mass density over two years while effectively alleviating pain symptoms. Despite being effective, all of treatments may have additional negative effects. The best approach to pharmacotherapy depends on the individual patient's needs and circumstances. Taking into consideretion potential effects, an appropriate dose or a combination of the above options should be performed. The treatment options of Relugolix and Linzagolix are both promising and well-tolerated. Further researches should focuse on long-term bone health monitoring strategies and its safety profile.

Cells residing in, and on, the calcified periodontal bone matrix experience numerous mechanical stimuli daily. The nature of the mechanical stimuli depends on whether the mechanical triggers are physiological, e.g., arising from masticatory forces, distributed via a healthy periodontal ligament to the alveolar bone, or represent "error-loads", e.g., arising during orthodontic tooth movement or around dental implants. Mechanosensitive osteocytes mediate osteoclast and osteoblast recruitment and activity in the presence of unloading, but "error loads" can directly activate signaling pathways in osteoblasts, thereby directing osteoblast activity and accumulating the bone mass essential for a functional masticatory system. Mitogen-activated protein kinases (MAPKs) play a pivotal role in regulating osteoblast growth, differentiation, and survival. This scoping review investigates which MAPKs are rapidly (within minutes) activated in osteoblasts in response to different types of mechanical stimuli. In the discussion, we tie the activation of MAPKs to altered osteoblast number and activity and the production of signaling factors. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we identified studies linking MAPKs, osteoblasts, and mechanical stress. The review included 33 in vitro studies. The findings revealed that extracellular signal-regulated kinases ERK1/2, p38, and JNK were rapidly activated in osteoblasts in response to various mechanical stimuli. Fluid flow forces, representing shear stress such as those present during mastication or orthodontic movement, activated all three MAPK branches. Substrate stretch, applied to simulate strain from mastication, induced a broad spectrum of responses. Hydrostatic pressure, often applied to reflect compression from implant loading or mastication, triggered all known MAPK pathways within an hour. In contrast, more selective stimuli such as low-intensity pulsed ultrasound and hypotonic pressure preferentially activated ERK1/2. Regardless of the stimulus, ERK1/2 was usually, and rapidly activated within minutes. In conclusion, diverse mechanical stimuli, including shear stress, substrate strain, and hydrostatic pressure, frequently, and rapidly, upregulate ERK1/2 signaling in osteoblasts. Given ERK1/2's established role in promoting osteoblast proliferation and differentiation, this early activation may help explain the localized bone formation observed under mechanical loading during orthodontic treatment, dental implant integration, or alveolar bone remodeling.

The circadian rhythm system plays an essential role in maintaining skeletal homeostasis, yet the precise impact of circadian rhythm abnormalities on bone mineral density (BMD) remains poorly understood. In this study, we systematically investigated the effects of rhythm disruption on bone metabolism by establishing murine models exposed to winter-simulated extended darkness (8-h light:16-h dark) and severe non-24-h light-dark cycles (8L:8D, 6L:6D, and 4L:4D). Our structural and histological analyses revealed that abnormal circadian rhythms profoundly uncouple bone remodeling, leading to a precipitous decline in trabecular bone mass. Crucially, we demonstrated that enhanced osteoclast activity due to the extended period of darkness in winter increases the risk of fractures, and this skeletal deterioration is further exacerbated under increasingly fragmented non-24-h rhythms. Mechanistically, circadian misalignment induced a severe downregulation of the Sirt3-SOD2 signaling pathway in bone tissue, which released physiological constraints on RANKL expression and subsequently drove rampant osteoclastogenesis. Pharmacological intervention with the endogenous circadian synchronizer melatonin partially mitigated this rhythm-disrupted bone loss by restoring Sirt3 expression and predominantly enhancing osteoblast anabolism; however, its capacity to directly suppress rhythm-induced osteoclast hyperactivation was limited. Furthermore, co-treatment with the Sirt3 inhibitor 3-TYP abolished the osteoprotective effects of melatonin by concurrently impairing osteoblast function. Collectively, these findings identify circadian rhythm disruption as a critical intrinsic driver of BMD decline. This chronobiological perspective elucidates that photoperiod-induced circadian disruptions may act as a risk factor for diminished bone density by driving osteoclastogenesis, warranting further translational research in humans.

Messenger RNA (mRNA) therapy represents a transformative platform in regenerative medicine, but its application to skeletal disorders remains limited by the pronounced hepatic tropism of conventional lipid nanoparticle (LNP) delivery systems. To redirect the distribution of biomolecules to bone tissue, we developed a bone-targeting mRNA nanocarrier (SA@LNP-D) through microfluidic synthesis followed by surface conjugation of the Asp8 peptide (binding to hydroxyapatite). This system enables efficient expression of anti-sclerostin antibody mRNA in bone tissue, thereby achieving therapeutic effects for osteoporosis treatment. Our invitro experimental results have demonstrated that LNP modified with bone-targeting peptides exhibits significant bone affinity and can efficiently bind to hydroxyapatite and isolated bone. Furthermore, the invivo results confirmed that SA@LNP-D effectively reduces hepatic sequestration and specifically accumulates in bones through mineral-directed anchoring. In a murine ovariectomy model of osteoporosis, systemic delivery of bone-targeted LNP demonstrated a stronger therapeutic effect compared to conventional LNP. It not only stimulated bone formation but also inhibited bone resorption, thereby significantly restoring trabecular bone mass and microstructure. Together, this work establishes a targeted, nonhepatic mRNA delivery strategy that offers a safe and effective therapeutic option for osteoporosis and related skeletal conditions.

Bone tissue represents a dynamic tissue that undergoes continuous renewal and remodeling through the coupled actions of osteoblast-driven bone formation and osteoclast-mediated bone resorption. Proper coupling between these two processes is essential for maintaining bone homeostasis, whereas its disruption leads to skeletal pathology. Excessive osteoclast activity underlies disorders such as osteoporosis and Paget's disease, while osteoclast deficiency, either quantitative or functional, results in osteopetrosis. Osteopetrosis comprises a group of genetically heterogeneous and clinically variable rare metabolic bone diseases characterized by increased bone mass. Clinically, osteopetrosis is commonly classified into severe autosomal recessive osteopetrosis (ARO), also known as infantile malignant osteopetrosis, intermediate ARO, milder autosomal dominant osteopetrosis, and X-linked recessive osteopetrosis. Effective treatment options for both severe and milder forms of osteopetrosis remain an unresolved clinical challenge. This review sheds light on the potential of cell-based and gene-modified cell therapies as emerging strategies for the treatment of osteopetrosis. Current cell-based therapy approaches increasingly focus on induced pluripotent stem cells, while recent advances in gene therapy enable the correction of causative genetic defects through viral vector-mediated gene transfer, CRISPR/Cas9-based genome editing, or RNA interference-mediated gene silencing. In addition, the therapeutic potentials of immunological approaches based on recombinant human interferon gamma-1b is discussed. Despite significant progress, sustained research efforts are still required to translate cell and gene-modified cell therapy into effective and personalized clinical treatments for osteopetrosis.

Excessive osteoclast activation disrupts bone homeostasis, contributing to osteoporosis (OP). While Runx2 is known to regulate osteoblast differentiation, its role in osteoclasts is less clear. Using conditional knockout models, we demonstrate that Runx2 directly drives osteoclast differentiation by regulating Ctsk transcription. However, its dual function in both osteoblasts and osteoclasts limits therapeutic potential. We identify Ip6k2 as a Runx2-interacting protein that enhances Runx2-dependent Ctsk transcription specifically in osteoclasts. Genetic deletion of Ip6k2 phenocopies Runx2 loss in osteoclasts, suppressing osteoclastogenesis and increasing bone mass without affecting osteoblast function. Notably, dual deletion of Runx2 and Ip6k2 yields no additive effects, indicating a shared regulatory pathway. Importantly, both genetic and pharmacological inhibition of Ip6k2 protect against estrogen deficiency- and age-induced bone loss. Collectively, our findings position Ip6k2 as a promising osteoclast-specific target and highlight that disruption of the Ip6k2-Runx2 complex may offer an effective strategy for OP treatment.

Osteoporosis (OP) is a multifactorial skeletal disorder marked by reduced bone mass and microstructural deterioration. We investigated potential diagnostic biomarkers and immunometabolic targets through integrated bioinformatics and machine learning analysis. Batch-corrected GEO transcriptomic data were analyzed by WGCNA to identify OPassociated modules. An optimal diagnostic model was established using 12 machine learning algorithms (113 combinations). Immune infiltration and pathway activity were evaluated by CIBERSORT and GSEA, and hub genes were validated by qRT-PCR in plasma samples. The best random forest-based model had good predictive performance for both the training dataset and validation dataset (AUC > 0.80). Ten hub genes were finally screened out as candidate diagnostic biomarkers: POLA1, ARAP1, MAP7D1, TSPYL2, MRPL4, PPP1R14D, INTS1, SMARCB1, DLK1, and FPGT. Functional analyses showed enrichment in immunerelated and metabolic pathways, including PI3K-Akt signaling and pentose phosphate metabolism. These genes correlated with immune cell alterations, such as CD8⁷ T cells, Th17 cells, and macrophages. qRT-PCR validation confirmed their significant differential expression in OP samples. This study underscores immune-metabolic dysregulation at the core of OP pathobiology. Although heterogeneity existed in external validation cohorts, and sample sizes were small, our integrative analysis pipeline enhances the precision and clinical relevance of potential biomarkers. The study concluded that this work identified ten possible diagnostic biomarkers, and provided a mechanism for understanding the interaction between immune metabolism and OP, which will help guide further research on precision diagnosis and treatment in OP.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterised by bone fragility and frequent fractures. While current treatments aim to preserve bone mass, there is no cure. Boost Brittle Bones Before Birth (BOOSTB4) is an international clinical trial investigating postnatal (n = 15) and prenatal plus postnatal (n = 3) infusions of fetal mesenchymal stem cells as a potential treatment for severe OI. Each BOOSTB4 participant received four stem cell doses at four-month intervals. Here we explore the experiences of parents and of healthcare professionals involved in BOOSTB4. In this qualitative study, one or both parents of children participating in BOOSTB4 took part after the second dose (T1: 16 families, 22 participants) and at least 6 months after the final dose (T2: 12 families, 16 participants). Professionals delivering BOOSTB4 participated in one interview (n = 13). Data were analysed using codebook thematic analysis. Decisions to participate in the trial were influenced by the potential for improved prognosis and limited alternative therapies. Parents felt reassurance because they were taking action and gratitude for access to expertise in OI. Balancing hope, expectations and uncertainty around treatment efficacy was challenging. Parents also expressed disappointment and uncertainty about treatment ending. Practical challenges included travel for treatment with a child with OI or late in pregnancy. Professionals noted the difficulty in managing parental expectations and the regulatory and logistical barriers of an international trial. Findings emphasised the need for clear communication before, during and after the trial, transparent information and trial designs that accommodate the needs of individual families.

To examine whether the combined assessment of low handgrip strength (HGS) and low adductor pollicis muscle thickness (APMT) represents a simple and integrated risk stratification approach for identifying adult women at increased likelihood of low muscle mass and low bone mass. In this cross-sectional study, 296 adult women aged 24-59 years were evaluated. HGS and APMT were measured using a manual dynamometer and anthropometric calipers, respectively. Muscle mass, bone mineral density, and femoral geometry were assessed through dual-energy x-ray absorptiometry. Low muscle mass and low bone mass were defined using established criteria. Low HGS and low APMT were categorized using data-derived cutoffs obtained through receiver operating characteristic curve analysis. Associations were examined using adjusted linear and logistic regression models. Both HGS and APMT were independently associated with muscle mass (P < 0.001) and femoral bone outcomes (P = 0.001 and P = 0.005, respectively). When categorized, the combination of low HGS and low APMT showed stronger associations with reduced muscle mass and low bone mass (OR: 7.52, 95% CI: 2.88-19.63; P < 0.001), including the femoral neck (OR: 7.20, 95% CI: 2.34-22.16; P < 0.001), lumbar spine (OR: 3.28, 95% CI: 1.02-10.56; P = 0.047), and at least one site (OR: 4.47, 95% CI: 1.62-12.36; P = 0.004). The combined assessment of HGS and APMT captures complementary dimensions of musculoskeletal health and may serve as a practical approach for preliminary risk stratification, particularly in resource-limited settings where access to standard diagnostic methods, such as dual-energy x-ray absorptiometry, remains limited.

Bu-Sui-Dan promotes angiogenesis to mitigate age-related osteoporosis via the ZEB1/Notch1 axis.

Osteoblast-specific deletion of NF-κB p65 enhances trabecular bone formation and BMP-2-induced osteogenesis in mice.

Subtype-specific bone mineralization defects and early treatment amelioration in murine models of autosomal recessive osteopetrosis revealed by Raman spectroscopy.

Recent studies suggest that cold temperature (CT) exposure contributes to osteoporosis. While the gut microbiota (GM) is a key regulator of host physiology, CT conditions significantly alter its composition. In this study, we found that co-housing with room temperature (RT) mice, as well as colonization with RT-donor GM, conferred protection against CT-induced bone loss. Using 16S rRNA gene sequencing, we demonstrated that the CT-triggered decline in intestinal Bifidobacterium pseudolongum (B. p) abundance was rescued by co-housing with RT mice. Furthermore, oral administration of B. p effectively alleviated CT-induced bone loss. Mechanistically, we identified that small extracellular vesicles derived from Bifidobacterium. pseudolongum (B. p-sEVs) were taken up by bone tissue, where they enhanced osteogenesis and suppressed pyroptosis in bone marrow stromal cells (BMSCs). Collectively, our findings suggest that the GM helps preserve bone mass via bacterial sEVs, and that the reduction of B. p and its derived sEVs drives CT-induced bone loss.

The role of the mesenchymal stem cell therapy in bone regeneration of osteoporosis: clinical translation and limitations.

Tamoxifen induces region-specific osteocytic recombination and transiently alters bone structure in Dmp1-Cre-ERT2 mice.

Background: Osteoporosis (OP) is a chronic disease characterized by decreased bone mass and altered microarchitecture, leading to bone fragility and fracture risk. To date, although carbohydrate-binding proteins Galectins 1 and 3 (Gal-1/Gal-3) have been implicated in bone metabolism, inflammation and aging, their levels and potential regulation by microRNAs (miRNAs) have not yet been investigated in OP. Methods: In this pilot study, 13 osteoporotic (OP) and 10 non-osteoporotic (NOP) patients, all undergoing hip or knee arthroplasty, were enrolled. Due to the unavailability of DXA measurements, OP classification was based on cortical bone ratio and distal femoral cortical index. Clinical parameters and blood samples were collected preoperatively, while bone biopsies were obtained intraoperatively. ELISA and qRT-PCR were used to quantify Gal-1, Gal-3, miR-22 and miR-21 in bones and sera. Correlations with clinical parameters were assessed. Results: Several OP biopsies exhibited a reduction in Gal-1 levels, whereas miR-22, Gal-3 and miR-21 were increased. Serum analysis revealed similar dysregulation patterns, with increased miR-21 and decreased Gal-1 and miR-22 levels in several OP patients. Conclusions: This pilot study suggests a putative association of Gal-1, Gal-3, and their previously reported related miRNAs with osteoporotic bone status, indicating their potential involvement in OP-related bone metabolism.

Spinal muscular atrophy (SMA), caused by mutations in survival motor neuron 1 (SMN1), presents with severe muscle atrophy and prevalent osteoporosis. Transcriptomic profiling of patient muscle biopsies revealed enrichment of extracellular vesicle genes, yet the contribution of SMA-EVs to SMA-associated bone loss and their link to SMN deficiency remain undefined. Clinical CT/MRI images of SMA and control subjects were acquired to quantify osteoporosis and muscle atrophy. SMA model mice (Smn1hSMN2/hSMN2ROSA26hSMN2/+) were phenotyped at 6 weeks by micro-CT and histology. EVs were isolated from muscles, validated (western blot, transmission electron microscope, nano-flow cytometry, BCA protein assay), and compared between genotypes. DiL-labelled EV biodistribution was tracked in vivo; uptake by BMSCs/BMMs was confirmed by confocal microscopy. Cytotoxicity was assessed by live/dead staining. Dose-response experiments evaluated the osteogenic and anti-osteoclastic activity of SMA-EVs. Comparison of the effects of SMA-EVs and CON-EVs were performed with adequate doses in vitro and in vivo, followed by EV replenishment in SMA mice. Osteogenic and osteoclastogenic gene expression was quantified by qPCR; ALP activity by ELISA. Bone and cell parameters were assessed by HE staining, TRAP staining, COL-1 immunofluorescence staining, and micro-CT. RNA-seq data were validated by Western blot. Lentiviral shRNA and over-expression plasmids were used to generate muscle cells with stable SNAP23 knock-down or up-regulation, and AAV-mediated muscle-specific Snap23 over-expression was employed in mice to define the role of muscular SNAP23 in EV secretion and its impact on bone mass. Mice carrying extra SMN2 transgenic copies were analyzed to delineate the SMN-SNAP23 relationship. SMA patients and mice exhibited a significantly diminished capacity of skeletal muscle to secrete EVs, which were readily internalized by BMSCs and BMMs, dose-dependently promote osteogenic differentiation and suppress osteoclast formation. Adequate-dose SMA-EVs matched CON-EVs efficacy, and SMA-EVs supplementation effectively rescued the osteoporotic phenotype in SMA. Transcriptomics indicated impaired SNARE complex-mediated vesicle secretion pathway. We further demonstrated that deficiency of SMN protein drives downregulation of its downstream key SNARE component, SNAP23, thereby impairing the efficiency of SMA-EV secretion. Our work elucidates a novel disease-specific mechanism for SMA osteoporosis-dysfunction of the SMN-SNAP23-EVs axis-and highlights the therapeutic potential of replenishing SMA-EVs or targeting this axis, offering a promising strategy to improve skeletal health in SMA.