Comprehensive analysis of circRNA expression profiles in postmenopausal women differing in bone mineral density.

Postmenopausal osteoporosis (PMOP) seriously endangers the bone health of older women. Although there are currently indicators to diagnose PMOP, early diagnostic biomarkers are lacking. Circular ribonucleic acid (circRNA) has a stable structure, regulates gene expression, participates in the pathological process of disease, and has the potential to become a biomarker. The purpose of this study was to investigate circRNAs that could be used to predict patients with early PMOP. Ribonucleic acid (RNA) sequencing was performed on peripheral blood leukocytes from 15 female patients to identify differential circRNAs between different groups. Using bioinformatics analysis, enrichment analysis was performed to discover relevant functions and pathways. CircRNA-micro ribonucleic acid (miRNA) interaction analysis and messenger ribonucleic acid (mRNA) prediction and network construction help us to understand the relationship between circRNA, miRNA, and mRNA. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the gene expression of candidate circRNAs. We screened out 2 co-expressed differential circRNAs, namely hsa_circ_0060849 and hsa_circ_0001394. By analyzing the regulatory network, a total of 54 miRNAs and 57 osteoporosis-related mRNAs were identified, which, as potential downstream target genes of hsa_circ_0060849 and hsa_circ_0001394, may play a key role in the occurrence and development of PMOP. The occurrence and development of PMOP is regulated by circRNAs, and hsa_circ_0060849 and hsa_circ_0001394 can be used as new diagnostic markers and therapeutic targets for early PMOP.

Correlation of serum anti-Mullerian hormone and Inhibin-B levels with osteoporosis of menopausal woman in Chinese Daur ethnic group.

PURPOSE: To investigate the diagnostic value of anti-Mullerian hormone (AMH) and Inhibin B (InhB) in menopausal women with osteoporosis from the Chinese Daur ethnic group. METHODS: A total of 175 menopausal women were selected and divided into the osteoporosis group (N = 90) and the control group (N = 85). BMD was measured by dual-energy X-ray absorptiometry, and laboratory indicators of osteoporosis, for example, serum osteocalcin (OC), ß-collagen special sequence (ß-CTX), and procollagen type I amino-terminal propeptide (PINP), bone alkaline phosphatase (BALP), AMH, and InhB were measured by commercial kits. The relationship between osteoporosis and AMH or InhB was analyzed. The predictive values of AMH and InhB were reflected by the ROC curve and logistic regression. RESULTS: The level of BMD was decreased and the levels of OC, ß-CTX, PINP, and BALP of the menopausal osteoporosis group were increased. The concentration of AMH and InhB in the menopausal osteoporosis group was decreased and they had connections with each other. AMH and InhB could be used as independent indicators for the occurrence of osteoporosis in menopausal women and their combination had a higher diagnostic value. CONCLUSION: AMH and InhB measurements in menopausal women had a certain clinical significance in the detection of osteoporosis. The occurrence of osteoporosis was related to BMD, OC, ß-CTX, BALP, AMH, and InhB.

Osteoporotic quality of life, self-efficacy, and fracture protection behaviors in postmenopausal women.

It is important for postmenopausal women to acquire bone health protective behaviors to protect them from fractures. For this reason, it is necessary to evaluate bone health during menopause and to inform women. PURPOSE: This study was conducted to examine osteoporotic fracture protection behaviors, quality of life, and self-efficacy in postmenopausal women. METHODS: In the study, the data were evaluated with the socio-demographic data form, Osteoporotic Fracture Protection Scale, Osteoporosis Self-Efficacy-Efficacy Scale, European Osteoporosis Foundation Quality of Life Questionnaire-41, which includes introductory information on socio-demographic characteristics. RESULTS: It was determined that the postmenopausal women included in our study were between the ages of 45-92; more than half of them had chronic diseases; their average BMI was 29; and their DEXA score was - 3.00 ± 0.41. Among the people included in our study, those with a history of fractures had lower self-efficacy scores. It was determined that the fracture prevention scale scores of the participants were above the average, and the average of the osteoporosis-related quality of life score was high. In addition, it was determined that there was a strong positive correlation between self-efficacy and fracture prevention scale. CONCLUSION: It is important to determine behaviors to prevent osteoporotic fractures in postmenopausal women, to raise the necessary awareness and to inform patients about the precautions to be taken. It is thought that it will increase patients' quality of life by increasing their disease-related self-efficacy. Therefore, there is a need for research on providing education to op patients and examining the results.

Bone loss after discontinuation of denosumab: the devil is in the details.

A 47-year-old postmenopausal woman with osteoporosis was treated with denosumab, which was discontinued due to side effects. She was therefore transitioned to a yearly intravenous infusion of zoledronic acid. An increase in bone turnover markers together with bone loss at the lumbar spine was observed before the second infusion, suggesting an overshooting of bone resorption due to denosumab discontinuation. On physical examination, the patient was restless and reported having lost about 10 kg since the last visit. A solitary left inferior thyroid nodule was noted on neck palpation. Circulating thyroid hormone levels were elevated, with suppressed thyroid-stimulating hormone. A thyroid scan showed increased uptake in the left inferior nodule with suppression of the remainder of the thyroid gland. A diagnosis of hyperthyroidism due to toxic adenoma was made. The patient was treated with radioactive iodine ablation, with consequent complete normalization of thyroid function. She continued yearly treatment with zoledronic acid. She remained clinically well with no further fractures. Bone turnover markers were appropriately suppressed and bone mineral density increased in the spine and hip. This case illustrates how the overshooting phenomenon following denosumab discontinuation may be compounded by the development of secondary conditions, which can result in suboptimal response to antiresorptive osteoporosis medications.

Plasma serotonin precursors and metabolite are correlated with bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis.

BACKGROUND: Serotonin (5-HT) precursors regulate bone remodeling. This study aims to investigate the correlation of plasma 5-HT precursors and metabolite with bone mineral density (BMD) and bone turnover markers in postmenopausal osteoporosis (PMOP) patients. METHODS: The age, body mass index (BMI), and years since menopause (YSM) were documented for 348 postmenopausal women in normal/osteopenia/osteoporosis (OP) groups, with lumbar spine and femoral neck BMD measured. Serum bone turnover markers (PINP/ß-CTX) and plasma 5-HT, 5-HT precursors (Trp/5-HTP) and metabolite (5-HIAA) were measured by ELISA. OP patients were allocated to high/low expression groups following ROC analysis of 5-HT/Trp/5-HTP/5-HIAA. The relationship of plasma 5-HT/Trp/5-HTP/5-HIAA, BMD, and bone turnover markers with PMOP was analyzed using logistic regression analysis. The correlation of plasma 5-HT/Trp/5-HTP/5-HIAA with BMD and bone turnover markers was analyzed using Pearson's correlation analysis, followed by logistic regression analysis of the relationship between plasma 5-HT/Trp/5-HTP/5-HIAA and BMD, bone turnover markers and PMOP. RESULTS: BMI, YSM, BMD and PINP, and ß-CTX levels differed among groups. Levels of plasma 5-HT precursors/metabolite were increased in OP patients. Individuals with high 5-HT precursors/metabolite levels had low BMD and high PINP/ß-CTX levels. The 5-HT precursors/metabolite negatively-correlated with BMD and positively-correlated with PINP/ß-CTX. BMI, YSM, BMD, and PINP/ß-CTX/Trp/5-HTP/5-HT related to PMOP and were independent risk factors for OP. CONCLUSION: Plasma 5-HT precursors and metabolite negatively-correlate with BMD and positively-correlate with PINP/ß-CTX in PMOP patients. Peripheral 5-HT precursors and metabolite level may be a new direction of treatment of PMOP and bone metabolism-related disorders.

The association of FRAX with predictors of falls in the assessment of postmenopausal osteoporosis in Turkey: the fracture study of Turkey (FRACT study).

Although FRAX is used for fracture risk evaluation, this tool does not include balance and fall risk. The association between the predictors of falls and high FRAX scores we found in this study suggests that risk indicators for falls may add substantial value to FRAX by improving fracture risk prediction. PURPOSE: This observational, descriptive, and cross-sectional study aimed to assess the fall risk predictors and explore their association with FRAX in Turkish patients with postmenopausal osteoporosis. METHODS: Two hundred and nine (209) women with postmenopausal osteoporosis referred to the Fracture Liaison Service (FLS) at Istanbul University-Cerrahpasa were enrolled in the FRACT study (The Fracture Study of Turkey). Clinical risk factors were assessed using the FRAX tool. Tandem stance, Tandem walking, Timed up and go (TUG), and Chair stand tests were performed to assess balance and fall risk. RESULTS: Among patients with a mean age of 67.6 (± 9.7) years, 66 patients (31.6%) had osteoporosis without fractures and 143 patients (68.4%) had fragility fractures. The proportion of patients with poor performance of fall prediction tests was significantly higher in patients with a fragility fracture than those with osteoporosis alone. There was an inverse relationship between dynamic balance tests and the reported number of prior falls in the past year. FRAX score was higher in patients with impaired Tandem stance, Tandem walking, and TUG tests (p = 0.008, p = 0.035, p = 0.001, respectively). CONCLUSION: Assessment of fall risk predictors should be one of the major pillars in the physical evaluation of osteoporotic patients in the FLS setting. FRAX is a useful tool to determine the fracture risk of patients with both static and dynamic balance impairments. Combining balance assessment with FRAX may be an important step to optimize osteoporosis risk assessment.

Mechanistic study on the alleviation of postmenopausal osteoporosis by Lactobacillus acidophilus through butyrate-mediated inhibition of osteoclast activity.

In China, traditional medications for osteoporosis have significant side effects, low compliance, and high costs, making it urgent to explore new treatment options. Probiotics have demonstrated superiority in the treatment of various chronic diseases, and the reduction of bone mass in postmenopausal osteoporosis (PMOP) is closely related to the degradation and metabolism of intestinal probiotics. It is crucial to explore the role and molecular mechanisms of probiotics in alleviating PMOP through their metabolites, as well as their therapeutic effects. We aim to identify key probiotics and their metabolites that affect bone loss in PMOP through 16srDNA sequencing combined with non-targeted metabolomics sequencing, and explore the impact and possible mechanisms of key probiotics and their metabolites on the progression of PMOP in the context of osteoporosis caused by estrogen deficiency. The sequencing results showed a significant decrease in Lactobacillus acidophilus and butyrate in PMOP patients. In vivo experiments confirmed that the intervention of L. acidophilus and butyrate significantly inhibited osteoclast formation and bone resorption activity, improved intestinal barrier permeability, suppressed B cells, and the production of RANKL on B cells, effectively reduced systemic bone loss induced by oophorectomy, with butyric acid levels regulated by L. acidophilus. Consistently, in vitro experiments have confirmed that butyrate can directly inhibit the formation of osteoclasts and bone resorption activity. The above research results indicate that there are various pathways through which L. acidophilus inhibits osteoclast formation and bone resorption activity through butyrate. Intervention with L. acidophilus may be a safe and promising treatment strategy for osteoclast related bone diseases, such as PMOP.

How to Suppress Mineral Loss and Stimulate Anabolism in Postmenopausal Bones with Appropriate Timing of Exercise and Nutrients.

Background. Bone Health and Osteoporosis Foundation (BHOF) reports that as of 2023, approximately 10 million of older Americans have osteoporosis and another 44 million have low bone density. Osteoporosis is a serious handicap for the elderly and, in particular, for estrogen-deficient postmenopausal women, as it increases the risk of debilitating bone weakness and fractures. The BHOF recommendations for prevention of osteopenia, osteoporosis and bone fractures are to perform weight-bearing and muscle-strengthening exercises and to take recommended amounts of daily calcium and vitamin D. Methods. The purpose of this review is to describe and discuss recent evidence-based research on how to effectively utilize timing of exercise and calorie intake for stimulation of postmenopausal bone anabolism, and to provide this new information in the form of specific and actionable recommendations. Results. The five evidence-based recommendations are as follows: 1. Select an appropriate circadian time of day for exercise; 2. Increase walking speed to raise the movement momentum; 3. Eat a weight-maintenance meal one or two hours before the exercise bout; 4. Sustain the duration of walking activity (impulse) for 40 to 45 min; and 5. Repeat effective exercise stimulus 7 to 8 h after the first one to double the anabolic effect. Osteogenesis can also be increased with subthreshold mechanical loading, where needed, under several special circumstances. Conclusions. This review should provide pragmatic actionable pointers on how to utilize the idiosyncratic bone responsiveness to timing of movement and meals to prevent osteoporosis and encourage research toward a better understanding of how bone detects adequacy of a mechanical stimulus and determines duration of necessary rest to recover its sensitivity to mechanical stimulation and nutrients.

Equivalence trial of proposed denosumab biosimilar GP2411 and reference denosumab in postmenopausal osteoporosis: the ROSALIA study.

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.

Denosumab is a biologic treatment that stops bone breakdown. This clinical trial evaluated how similar GP2411 (a denosumab biosimilar in development) is compared with European-approved reference denosumab in women with post-menopausal osteoporosis. Biosimilars are highly similar to the original treatment ('reference denosumab') and may have a lower price. 263 patients were randomly assigned to receive GP2411 and 264 to reference denosumab. Treatment was given at the study beginning, at Week 26 and at Week 52. 124 patients were re-assigned at Week 52 to test the effect of changing from reference denosumab to GP2411. The study showed similarity in how the body interacts with the treatments, what effects the treatment has (both measured over 26 weeks), and bone mineral density (measured over 78 weeks). Antibody responses to GP2411 were detected in similar proportions of patients on each treatment. Reported adverse events were similar between treatments before Week 52, and from Week 52 to 78, and <5% of patients experienced serious adverse events. A change of treatment from reference denosumab to GP2411 did not affect outcomes. These results showed similarity between GP2411 and reference denosumab in this population. In future, GP2411 may enable more patients to benefit from denosumab.

Duration of fracture prevention after zoledronate treatment in women with osteopenia: observational follow-up of a 6-year randomised controlled trial to 10 years.

BACKGROUND: We previously identified that zoledronate administered at 18-month intervals reduced fragility fractures by a third in a 6-year trial of women older than 65 years with osteopenia. This extension aims to identify the persistence of these effects. METHODS: Of the 2000 ambulant, community dwelling, postmenopausal women older than 65 years recruited in Auckland, New Zealand, with T-scores at the total hip or femoral neck in the range -1·0 to -2·5, we invited participants who received four doses of intravenous zoledronate, completed follow-up to year 6 of the core trial, did not have metabolic bone disease (other than osteoporosis), and were not using bone-active drugs into this 4-year observational study extension, during which further treatment was at the discretion of their own doctors. Participants were asked to notify study staff of any new fractures and were telephoned at 7·5 years and 9·0 years to update their health status. Participants were then invited to an onsite visit at 10·0 years. Fractures and other health events were documented at each contact and analysed in all women who entered the extension, and bone mineral density (BMD; analysed in participants without notable use of bone-active medications who attended an onsite visit at 10 years) and turnover markers (measured from fasting morning blood in a random subset of 50 participants) were measured at year 10. FINDINGS: Of the 1000 women randomly assigned to receive zoledronate in the core trial, 796 participants were eligible for the extension, of whom 762 (96%) entered the extension between Sept 24, 2015, and Dec 13, 2017. Mean follow-up duration was 4·24 years (SD 0·57, range 0·61-6·55; final follow-up on May 25, 2022). 727 (91%) of participants were assessed at 10 years. 25 women died during the extension, six withdrew for medical reasons, and four were lost to follow-up. 92 women suffered 114 non-vertebral fractures during the extension. Non-vertebral fracture rates increased from a nadir of 15 fractures per 1000 woman-years (95% CI 10-21) in the last 2 years of the core trial to 24 fractures (17-33) in years 6-8 and 42 fractures (32-53) in years 8-10, similar to that in the placebo group in the last 2 years of the core trial. Total hip BMD (relative risk per 0·1 g/cm2 0·73, 95% CI 0·57-0·93; p=0·011) and a previous history of non-vertebral fracture (1·74, 1·12-2·69; p=0·013) at year 6 predicted incident fractures but change in total hip BMD did not. Total hip BMD decreased from 4·2% above study baseline to 0·8% above baseline (p<0·0001) during the extension. Turnover markers were not useful for predicting BMD loss in individuals. Osteonecrosis of the jaw or atypical femoral fractures did not occur in any participants. INTERPRETATION: The reduced fracture rates following zoledronate in the core trial were substantially maintained for 1·5-3·5 years after the last zoledronate infusion, but not thereafter. FUNDING: Health Research Council of New Zealand.

The bone-protective benefits of kaempferol combined with metformin by regulation of osteogenesis-angiogenesis coupling in OVX rats.

This study was to investigate the potential mechanisms of treatment with metformin (Met) combined with kaempferol (Kae) against postmenopausal osteoporosis. Experiments were conducted in both ovariectomy (OVX)-induced osteoporosis rats and in vitro using RAW264.7 cells, MC3T3-E1 cells, and HUVECs. Results demonstrated the therapeutic effect of Met combined with Kae on osteoporosis. In vivo, Kae alone and in combination with Met treatments enhanced tibial trabecular microstructure, bone mineral density (BMD), and mechanical properties in OVX rats without causing hepatotoxicity and nephrotoxicity. It also reduced bone resorption markers (CTX-1 and TRAP) and increased the bone formation marker (PINP) level in the serum of OVX rats. The expression of bone resorption marker TRAP was reduced, while bone formation markers Runx2 and ALP were enhanced in the bone tissue of OVX rats. Furthermore, Met combined with Kae also promoted the expression of angiogenesis-related markers CD31 and VEGF in OVX rats. In vitro, MC3T3-E1s cells treated with Met combined with Kae showed higher expression of ALP, Runx2, and VEGF. Interestingly, the treatment did not directly promote HUVECs migration and angiogenesis, but enhanced osteoblast-mediated angiogenesis by upregulating VEGF levels. Additionally, Met combined with Kae treatment promoted VEGF secretion in MC3T3-E1, and activated the Notch intracelluar pathway by upregulating HES1 and HEY1 in HUVECs. Meantime, their stimulation on CD31 expression were inhibited by DAPT, a Notch signaling inhibitor. Overall, this study demonstrates the positive effects of Met combined with Kae on osteoporotic rats by promoting osteogenesis-angiogenesis coupling, suggesting their potential application in postmenopausal osteoporosis.

Interferon Regulatory Factor 4 (IRF4) Plays a Key Role in Osteoblast Differentiation of Postmenopausal Osteoporosis.

BACKGROUND: Postmenopausal osteoporosis (PMOP) is a prevalent disease, which features decreased bone mass, bone weakness and deteriorated bone microstructure in postmenopausal women. Although many factors have been revealed to contribute to the occurrence of PMOP, its mechanism remains undefined. This work aimed to identify significant changes in gene expression during PMOP formation and to examine the most valuable differential genes in postmenopausal osteoporosis versus the control group. METHODS: The GSE68303 dataset that contains 12 ovariectomize (OVX) experimental and 11 sham groups was downloaded and analyzed. The results indicated that interferon regulatory factor 4 (IRF4) might be a hub gene in the development of postmenopausal osteoporosis. Western blot and immunohistochemistry were carried out to evaluate IRF4 levels in thoracic vertebra extracts from OVX and Sham mice. To assess IRF4's impact on osteogenic differentiation in postmenopausal bone marrow mesenchymal stem cells (BM-MSCs), IRF4 overexpression (OV-IRF4) and knockdown (Sh-IRF4) plasmids were constructed. RESULTS: The results showed that comparing with the sham group, bone samples from the OVX group showed higher IRF4 expression. Alkaline phosphatase (ALP) staining revealed that IRF4 overexpression significantly inhibited ALP activity, while IRF4 knockdown promoted ALP activity in BM-MSCs. Simvastatin-treated OVX mice showed increased total bone volume/total tissue volume (BV/TV) and elevated Runx2 expression by immunohistochemical staining compared with the OVX group. CONCLUSIONS: This study demonstrated that IRF4 is associated with OVX induced osteoporosis, it can regulate bone stability by inhibiting the osteogenic differentiation BM-MSCs. This study may help enhance our understanding of the molecular mechanism of PMOP formation, providing new insights into estrogen defiance induced osteoporosis.

Early changes of bone metabolites and lymphocyte subsets may participate in osteoporosis onset: a preliminary study of a postmenopausal osteoporosis mouse model.

Purpose: Metabolic and immune changes in the early stages of osteoporosis are not well understood. This study aimed to explore the changes in bone metabolites and bone marrow lymphocyte subsets and their relationship during the osteoporosis onset. Methods: We established OVX and Sham mouse models. After 5, 15, and 40 days, five mice in each group were sacrificed. Humeri were analyzed by microCT. The bone marrow cells of the left femur and tibia were collected for flow cytometry analysis. The right femur and tibia were analyzed by LC-MS/MS for metabolomics analysis. Results: Bone microarchitecture was significantly deteriorated 15 days after OVX surgery. Analysis of bone metabolomics showed that obvious metabolite changes had happened since 5 days after surgery. Lipid metabolism was significant at the early stage of the osteoporosis. The proportion of immature B cells was increased, whereas the proportion of mature B cells was decreased in the OVX group. Metabolites were significantly correlated with the proportion of lymphocyte subsets at the early stage of the osteoporosis. Conclusion: Lipid metabolism was significant at the early stage of the osteoporosis. Bone metabolites may influence bone formation by interfering with bone marrow lymphocyte subsets.

Association of neutrophil to lymphocyte ratio with bone mineral density in post-menopausal women: a systematic review and meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis to compare the neutrophil lymphocyte ratio (NLR) levels between women with post-menopausal osteopenia or osteoporosis to those with normal bone mineral density (BMD). METHODS: We used Web of Science, PubMed, and Scopus to conduct a systematic search for relevant publications published before June 19, 2022, only in English language. We reported standardized mean difference (SMD) with a 95% confidence interval (CI). Because a significant level of heterogeneity was found, we used the random-effects model to calculate pooled effects. We used the Newcastle-Ottawa scale for quality assessment. RESULTS: Overall, eight articles were included in the analysis. Post-menopausal women with osteoporosis had elevated levels of NLR compared to those without osteoporosis (SMD = 1.03, 95% CI = 0.18 to 1.88, p = 0.017, I2 = 98%). In addition, there was no difference between post-menopausal women with osteopenia and those without osteopenia in neutrophil lymphocyte ratio (NLR) levels (SMD = 0.58, 95% CI=-0.08 to 1.25, p = 0.085, I2 = 96.8%). However, there was no difference between post-menopausal women with osteoporosis and those with osteopenia in NLR levels (SMD = 0.75, 95% CI=-0.01 to 1.51, p = 0.05, I2 = 97.5%, random-effect model). CONCLUSION: The results of this study point to NLR as a potential biomarker that may be easily introduced into clinical settings to help predict and prevent post-menopausal osteoporosis.

Machine learning predicts the risk of osteoporosis in patients with breast cancer and healthy women.

OBJECTIVE: In this study, we investigated the effects of endocrine therapy and related drugs on the body composition and bone metabolism of patients with breast cancer. Additionally, using body composition-related indicators in machine learning algorithms, the risks of osteoporosis in patients with breast cancer and healthy women were predicted. METHODS: We enrolled postmenopausal patients with breast cancer who were hospitalized in a tertiary hospital and postmenopausal women undergoing health checkups in our hospital between 2019 and 2021. The basic information, body composition, bone density-related indicators, and bone metabolism-related indicators of all the study subjects were recorded. Machine learning models were constructed using cross-validation. RESULTS: Compared with a healthy population, the body composition of patients with breast cancer was low in bone mass, protein, body fat percentage, muscle, and basal metabolism, whereas total water, intracellular fluid, extracellular fluid, and waist-to-hip ratio were high. In patients with breast cancer, the bone mineral density (BMD), Z value, and T value were low and the proportion of bone loss and osteoporosis was high. BMD in patients with breast cancer was negatively correlated with age, endocrine therapy status, duration of medication, and duration of menopause, and it was positively correlated with body mass index (BMI) and basal metabolism. The parameters including body composition, age, hormone receptor status, and medication type were used for developing the machine learning model to predict osteoporosis risk in patients with breast cancer and healthy populations. The model showed a high accuracy in predicting osteoporosis, reflecting the predictive value of the model. CONCLUSIONS: Patients with breast cancer may have changed body composition and BMD. Compared with the healthy population, the main indicators of osteoporosis in patients with breast cancer were reduced nonadipose tissue, increased risk of edema, altered fat distribution, and reduced BMD. In addition to age, duration of treatment, and duration of menopause, body composition-related indicators such as BMI and basal metabolism may be considerably associated with BMD of patients with breast cancer, suggesting that BMD status can be monitored in clinical practice by focusing on changes in the aforementioned indexes, which may provide a way to prevent preclinical osteoporosis.

Heterogeneous osteoimmune profiles via single-cell transcriptomics in osteoporotic patients who fail bisphosphonate treatment.

Postmenopausal osteoporosis arises from imbalanced osteoclast and osteoblast activity, and mounting evidence suggests a role for the osteoimmune system in bone homeostasis. Bisphosphonate (BP) is an antiresorptive agent, but its treatment failure rate can be as high as 40%. Here, we performed single-cell RNA sequencing on peripheral immune cells from carefully selected postmenopausal women: non-osteoporotic, osteoporosis improved after BP treatment, and BP-failed cases. We found an increase in myeloid cells in patients with osteoporosis (specifically, T cell receptor+ macrophages). Furthermore, lymphoid lineage cells varied significantly, notably elevated natural killer cells (NKs) in the BP-failed group. Moreover, we provide fruitful lists of biomarkers within the immune cells that exhibit condition-dependent differences. The existence of osteoporotic- and BP-failure-specific cellular information flows was revealed by cell-cell interaction analysis. These findings deepen our insight of the osteoporosis pathology enhancing comprehension of the role of immune heterogeneity in postmenopausal osteoporosis and BP treatment failure.

TNF-α promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) is a common kind of osteoporosis that is associated with excessive osteocyte death and bone loss. Previous studies have shown that TNF-α-induced osteocyte necroptosis might exert a stronger effect on PMOP than apoptosis, and TLR4 can also induce cell necroptosis, as confirmed by recent studies. However, little is known about the relationship between TNF-α-induced osteocyte necroptosis and TLR4. In the present study, we showed that TNF-α increased the expression of TLR4, which promoted osteocyte necroptosis in PMOP. In patients with PMOP, TLR4 was highly expressed at skeletal sites where exists osteocyte necroptosis, and high TLR4 expression is correlated with enhanced TNF-α expression. Osteocytes exhibited robust TLR4 expression upon exposure to necroptotic osteocytes in vivo and in vitro. Western blotting and immunofluorescence analyses demonstrated that TNF-α upregulated TLR4 expression in vitro, which might further promote osteocyte necroptosis. Furthermore, inhibition of TLR4 by TAK-242 in vitro effectively blocked osteocyte necroptosis induced by TNF-α. Collectively, these results suggest a novel TLR4-mediated process of osteocyte necroptosis, which might increase osteocyte death and bone loss in the process of PMOP.

Association between lumbar muscle size and bone mineral density in nonfractured postmenopausal women with and without osteoporosis.

OBJECTIVE: Estrogen deficiency in postmenopausal women is associated with bone loss and a decline in muscle mass. However, the associations between lumbar muscle size and bone mineral density (BMD) in postmenopausal women with and without osteoporosis remain unclear. The aim of this study was to investigate the associations between lumbar muscle size and BMD in nonfractured postmenopausal women with osteoporosis and those with osteopenia. METHODS: A total of 89 postmenopausal women with osteopenia (n = 53) and osteoporosis (n = 36) were retrospectively enrolled in this study from 2014 to 2022. All participants underwent lumbar magnetic resonance imaging and dual-energy absorptiometry within a month. The lean lumbar muscle sizes at different lumbar levels were quantitatively evaluated on axial T1-weighted images. The associations between lumbar muscle size and BMD were analyzed using Pearson's correlation analysis. RESULTS: The osteoporosis group had significantly smaller lean psoas muscle sizes than the osteopenia group. Based on the correlation analysis, the erector spinae and multifidus muscle sizes were significantly associated with lumbar and femoral neck BMDs in the osteoporosis group. However, no significant association was found between lean psoas muscle size and BMDs in the osteopenia group. Thus, the associations between lumbar muscle decline and bone loss differed between postmenopausal women with osteoporosis and those with osteopenia. CONCLUSIONS: The study findings suggest differences in the associations between BMD and lumbar muscle size between postmenopausal women with osteoporosis and those with osteopenia.