Accelerated Bone Loss Research Articles

Osteoporosis in older men

Osteoporosis, characterized by reduced bone mass and compromised skeletal microarchitecture, significantly increases the risk of fractures and is the most prevalent metabolic bone disease. While it is commonly associated with post-menopausal women, osteoporosis and subsequent fractures are also substantial concerns in men. Men experience sustained bone loss after the sixth decade, with estimates indicating that 20% of Americans with osteopenia or osteoporosis are men. Approximately one in eight men over 50 will suffer an osteoporotic fracture, with hip fractures in men leading to a two- to threefold increase in mortality compared to women. The prevalence of osteoporosis in men has risen, doubling in prevalence since the early 1990s. Men generally have higher peak bone mass and greater bone size, offering some protection against osteoporosis; however, aging leads to increased bone resorption and decreased bone formation, exacerbated by lower androgen and estrogen levels. Secondary causes, such as hypogonadism and chronic glucocorticoid use, are prevalent in men. Diagnosis primarily involves bone mineral density (BMD) measurements using dual-energy X-ray absorptiometry (DXA), with fracture risk assessment tools like FRAX and MORES aiding in clinical decisions. Treatment includes calcium and vitamin D supplementation, bisphosphonates, denosumab, and anabolic agents like teriparatide and abaloparatide. Special considerations are necessary for men undergoing androgen deprivation therapy for prostate cancer due to accelerated bone loss. Effective management requires early diagnosis, lifestyle modifications, and appropriate pharmacological interventions to reduce fracture risk and improve patient outcomes.

Accelerated bone loss in late reproductive-aged and perimenopausal women with vitamin D insufficiency.

The association between serum vitamin D levels and bone mineral density (BMD) varies by race and gender. This study aimed to evaluate this relationship between serum vitamin D levels and BMD, and changes of BMD over time in Korean women. We analyzed data from 586 generally healthy Korean women aged 29-79 who underwent health check-ups at Seoul National University Gangnam Center between 2010 and 2011 (baseline measurement) and 2015-2016 (follow-up). Dual energy X-ray absorptiometry (DEXA) and serum 25-hydroxyvitamin D (25OH-D) level measurements were conducted. We assessed the association between serum 25OH-D levels and BMD, as well as changes in BMD over time. The mean age of participants was 51.3 ± 7.9years, with a mean follow-up interval of 4.6 ± 0.7years, and mean serum 25OH-D level of 20.6 ± 8.5ng/ml. Baseline serum 25OH-D levels did not correlate with BMD values at the lumbar spine, femoral neck, or total femur, nor with changes in BMD over time. A significant negative association was found between perimenopausal status and BMD changes at all sites, and between premenopausal status and lumbar bone mass, compared to postmenopausal status in the 25OH-D < 20ng/ml group. This association was not observed in women with higher serum 25OH-D levels. Serum 25OH-D levels did not correlate with BMD levels or changes in BMD overall. However, in late reproductive-aged and perimenopausal women with serum 25OH-D insufficiency, there was a significant association with accelerated bone loss.

Risperidone accelerates bone loss in mice models of schizophrenia by inhibiting osteoblast autophagy

BackgroundRisperidone (RIS) is the first-line drug in the clinical treatment of schizophrenia, and long-term use may lead to bone loss and even osteoporosis. This study investigated whether the mechanism of RIS-induced bone loss is related to autophagy. MethodsThe schizophrenia mice were established with the administration of MK-801. Then, RIS were injected, or autophagy inducer rapamycin (RAPA) co-injected for 8 weeks. Cognitive performance was determined by the novel object recognition and Open field tests. Bone loss of schizophrenia mice were assessed using microCT, H&E staining, ALP staining, ARS staining and WB, respectively. Autophagy of schizophrenia mice were detected by immunofluorescence, transmission electron microscopy (TEM) and WB, respectively. In addition, osteogenic differentiation of MC3T3-E1 and BMSCs cells were assessed using H&E staining, ALP staining, ARS staining and WB, respectively. ResultsIn the present study, we found that RIS treatment can promote bone loss in schizophrenia mice and inhibit osteogenic differentiation of MC3T3-E1 and BMSCs cells. Interesting, the number of autophagosome and autophagy-related protein expression were decreased after RIS treatment. However, the bone loss and inhibition of osteogenic differentiation induced by RIS in schizophrenia mice were reversed by autophagy inducer RAPA. ConclusionRIS significantly increased bone loss and inhibited osteogenic differentiation in schizophrenia mice; the underlying mechanism entails suppressing osteoblast autophagy.

Delay the progression of glucocorticoid-induced osteoporosis: Fraxin targets ferroptosis via the Nrf2/GPX4 pathway.

Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.

Osteoclast-derived exosomes influence osteoblast differentiation in osteoporosis progression via the lncRNA AW011738/ miR-24-2-5p/ TREM1 axis

AimsTo investigate the molecular mechanism of osteoclast-derived exosomes in osteoporosis. Main methodsRANKL induced osteoclast model was screened for significantly differentially expressed lncRNAs and mRNAs by whole RNA sequencing. Exosomes were characterized using electron microscopy, western blotting and nanosight. Overexpression or knockdown of AW011738 was performed to explore its function. The degree of osteoporosis in an osteoporosis model was assessed by mirco-CT. The osteoclast model, osteoblast differentiation ability and the molecular mechanism of lncRNA AW011738/miR-24-2-5p/TREM1 axis in osteoporosis were assessed by dual luciferase reporter gene assay, Western blotting (WB), immunofluorescence and ALP staining. Bioinformatics was used to predict interactions of key osteoporosis-related genes with miRNAs, transcription factors, and potential drugs after upregulation of AW011738. To predict the protein-protein interaction (PPI) network associated with key genes, GO and KEGG analyses were performed on the key genes. The ssGSVA was used to predict changes in the immune microenvironment. Key findingsOsteoclast-derived exosomes containing lncRNA AW011738 decreased the osteogenesis-related markers and accelerated bone loss in OVX mice. Osteoclast (si-AW011738)-derived exosomes showed a significant increase in biomarkers of osteoblast differentiation in vitro compared to the si-NC group. As analyzed by mirco-CT, tail vein injected si-AW011738 OVX mice were less osteoporotic than the control group. AW011738 inhibited osteoblast differentiation by regulating TREM1 expression through microRNA. Meanwhile, overexpression of miR-24-2-5p inhibited TREM1 expression to promote osteoblast differentiation. SignificanceOsteoclast-derived exosomes containing lncRNA AW011738 inhibit osteogenesis in MC3T3-E1 cells through the lncRNA AW011738/miR-24-2-5p/TREM1 axis and exacerbate osteoporosis in OVX mice.

Altered extracellular matrix and mechanotransduction gene expression in rat bone tissue following long-term estrogen deficiency.

Osteoporosis is primarily associated with bone loss, but changes in bone tissue matrix composition and osteocyte mechanotransduction have also been identified. However, the molecular mechanisms underlying these changes and their relation to bone loss are not fully understood. The objectives of this study were to (1) conduct comprehensive temporal gene expression analyses on cortical bone tissue from ovariectomized rats, with a specific focus on genes known to govern matrix degradation, matrix production, and mechanotransduction, and (2) correlate these findings with bone mass, trabecular and cortical microarchitecture, and mineral and matrix composition. Microarray data revealed 35 differentially expressed genes in the cortical bone tissue of the ovariectomized cohort. We report that catabolic gene expression abates after the initial accelerated bone loss period, which occurs within the first 4wk of estrogen deficiency. However, in long-term estrogen deficiency, we report increased expression of genes associated with extracellular matrix deposition (Spp1, COL1A1, COL1A2, OCN) and mechanotransduction (Cx43) compared with age-matched controls and short-term estrogen deficiency. These changes coincided with increased heterogeneity of mineral-to-matrix ratio and collagen maturity, to which extracellular matrix markers COL1A1 and COL1A2 were positively correlated. Interestingly, mineral heterogeneity and collagen maturity, exhibited a negative correlation with PHEX and IFT88, associated with mechanosensory cilia formation and Hedgehog (Hh) signaling. This study provides the first insight into the underlying mechanisms governing secondary mineralization and heterogeneity of matrix composition of bone tissue in long-term estrogen deficiency. We propose that altered mechanobiological responses in long-term estrogen deficiency may play a role in these changes.

Denosumab Prevents Bone Loss and Microarchitectural Deterioration in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression Therapy: A Randomized Controlled Trial.

Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted. Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

Effects of Metabolic Dysfunction-Associated Steatotic Liver Disease on Bone Density and Fragility Fractures: Associations and Mechanisms.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has profound adverse effects on bone health and homeostasis. MASLD appears to be associated with changes in bone mineral density (BMD) and fracture rate. However, the data are ambiguous and conflicting. Although several studies have shown that children and adolescents with MASLD have decreased BMD, the data on the prevalence of fragility fractures among children are scarce. In adults, increasing evidence suggests that MASLD decreases BMD and increases the risk of fragility fractures, which appears to be due to deterioration of bone architecture in addition to a decrease in BMD. Effects of MASLD on bone health may also be age- and race-specific. MASLD does not seem to increase fracture risk in children and adolescents but increases the risk of fractures in elderly men, especially those of Asian origin. From a mechanistic perspective, bone remodeling is a continuous process between osteoblasts (bone-forming) and osteoclasts (bone-resorbing), with any imbalance resulting in metabolic bone disease. In individuals with MASLD, loss of anabolic insulin receptor signaling (insulin resistance) in osteoblasts and increased receptor activator of nuclear factor κB (RANK)/RANK ligand signaling in osteoclasts (proinflammatory cytokines) swings the pendulum toward accelerated bone loss. These processes are further complicated by the concomitant presence of obesity, type 2 diabetes mellitus, or sarcopenia in individuals with MASLD. This study reviews the current literature associated with the effects of MASLD on BMD and fragility fractures in children/adolescents and adults. This review also discusses the pathomechanisms that link MASLD with changes in BMD and fragility fractures.

Debulking of the Femoral Stem in a Primary Total Hip Joint Replacement: A Novel Method to Reduce Stress Shielding.

In current-generation designs of total primary hip joint replacement, the prostheses are fabricated from alloys. The modulus of elasticity of the alloy is substantially higher than that of the surrounding bone. This discrepancy plays a role in a phenomenon known as stress shielding, in which the bone bears a reduced proportion of the applied load. Stress shielding has been implicated in aseptic loosening of the implant which, in turn, results in reduction in the in vivo life of the implant. Rigid implants shield surrounding bone from mechanical loading, and the reduction in skeletal stress necessary to maintain bone mass and density results in accelerated bone loss, the forerunner to implant loosening. Femoral stems of various geometries and surface modifications, materials and material distributions, and porous structures have been investigated to achieve mechanical properties of stems closer to those of bone to mitigate stress shielding. For improved load transfer from implant to femur, the proposed study investigated a strategic debulking effort to impart controlled flexibility while retaining sufficient strength and endurance properties. Using an iterative design process, debulked configurations based on an internal skeletal truss framework were evaluated using finite element analysis. The implant models analyzed were solid; hollow, with a proximal hollowed stem; FB-2A, with thin, curved trusses extending from the central spine; and FB-3B and FB-3C, with thick, flat trusses extending from the central spine in a balanced-truss and a hemi-truss configuration, respectively. As outlined in the International Organization for Standardization (ISO) 7206 standards, implants were offset in natural femur for evaluation of load distribution or potted in testing cylinders for fatigue testing. The commonality across all debulked designs was the minimization of proximal stress shielding compared to conventional solid implants. Stem topography can influence performance, and the truss implants with or without the calcar collar were evaluated. Load sharing was equally effective irrespective of the collar; however, the collar was critical to reducing the stresses in the implant. Whether bonded directly to bone or cemented in the femur, the truss stem was effective at limiting stress shielding. However, a localized increase in maximum principal stress at the proximal lateral junction could adversely affect cement integrity. The controlled accommodation of deformation of the implant wall contributes to the load sharing capability of the truss implant, and for a superior biomechanical performance, the collared stem should be implanted in interference fit. Considering the results of all implant designs, the truss implant model FB-3C was the best model.

Astaxanthin prevents bone loss in osteoporotic rats with palmitic acid through suppressing oxidative stress

ABSTRACT Objectives The study aimed to assess the role of Astaxanthin (ATX) in palmitic acid(PA) -induced bone loss in Ovariectomized(OVX) rats. Methods In the OVX rat model, we observed that PA affects bone metabolism and accelerates bone loss. Additionally, treatment with ATX was able to suppress the deleterious effects of PA and a simultaneous decrease in serum MDA levels and an increase in SOD was observed. Results In addition, rats treated with ATX were observed to have significantly increased bone mass and elevated activity of SIRT1 and SOD2 in bone tissue. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclast differentiation, the ATX intervention was able to significantly restore the restriction of osteogenic differentiation and the up-regulation of osteoclast differentiation with PA therapy. Furthermore, we confirm that PA damage to cells is caused by increased oxidative stress, and that ATX can target and modulate the activity of SIRT1 to regulate the levels of oxidative stress in cells. Conclusion Summarizing, ATX may inhibit PA-induced bone loss through its antioxidant properties via the SIRT1 signaling pathway.

More rapid bone mineral density loss in older men with diabetes: The Osteoporotic Fractures in Men (MrOS) Study.

Type 2 diabetes mellitus (T2D) is associated with more rapid bone loss in women, but less evidence is available for men or those with prediabetes. To determine whether bone loss rate is affected by diabetes status in older men, we analyzed data from the Osteoporotic Fractures in Men (MrOS) study. The multisite MrOS study enrolled 5,994 men aged ≥65 years. Diabetes status was defined by self-report, diabetes medication use, or elevated fasting serum glucose at baseline. Hip bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA) at baseline and a follow-up visit after 4.6 ± 0.4 years. This analysis included 4095 men, excluding those without a follow-up DXA or with unknown diabetes status. Changes in hip BMD in participants with normoglycemia (NG), prediabetes, or T2D, excluding thiazolidinedione (TZD) users, were evaluated using generalized linear models (GLM). Diabetes medication use and BMD loss among those with T2D were also evaluated with GLM. In adjusted models, loss in hip BMD was greater in men with T2D (- 2.23%: 95% CI: -2.54 to -1.91; p<0.001) but not in men with prediabetes (-1.45%; 95% CI -1.63 to -1.26; p=0.33) compared to NG (-1.57%: 95% CI -1.73 to -1.41). Among men with T2D, TZD, insulin and sulfonylurea use were associated with greater hip BMD loss. Men with T2D, but not prediabetes, experienced an accelerated bone loss compared to participants with normoglycemia. More rapid bone loss predicts increased risk of fractures and mortality in broader populations.

Down-expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenesis and accelerates age-related bone loss via PTEN/PI3K/AKT pathway.

To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism. In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed. The CM and exosomes collected from senescent MLO-Y4 cells inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing detected significantly lower expression of miR-494-3p in senescent MLO-Y4 cell-derived exosomes compared with normal exosomes. The upregulation of exosomal miR-494-3p by miRNA mimics attenuated the effects of senescent MLO-Y4 cell-derived exosomes on osteogenic differentiation. Luciferase reporter assay demonstrated that miR-494-3p targeted phosphatase and tensin homolog (PTEN), which is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overexpression of PTEN or inhibition of the PI3K/AKT pathway blocked the functions of exosomal miR-494-3p. In SAMP6 mice, senescent MLO-Y4 cell-derived exosomes accelerated bone loss, which was rescued by upregulation of exosomal miR-494-3p. Reduced expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenic differentiation and accelerates age-related bone loss via PTEN/PI3K/AKT pathway.

Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss

The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3’-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis

BackgroundThe vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA.MethodsSixteen- to 18-month-old αCGRP-deficient mice (αCGRP−/−aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP−/−CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography.ResultsWTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP−/−aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP−/−aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA.ConclusionsSimilar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis.

The use of menopausal hormone therapy (MHT) has declined due to concerns about its potential side effects. However, its pivotal role in managing postmenopausal osteoporosis is gaining increased recognition. In this article, we explore how MHT assists postmenopausal women in maintaining bone health and preventing fractures. Recent research indicates that MHT significantly reduces the risk of fractures in women. This benefit is evident regardless of a woman's bone mineral density or their use of progestogens. However, there is limited evidence suggesting that the skeletal benefits continue once the treatment is discontinued. Possible complications of MHT include heart attacks, clots, strokes, dementia, and breast cancer. The most suitable candidates for MHT are women who have recently entered menopause, are experiencing menopausal symptoms, and are below 60 years of age with a minimal baseline risk of adverse events. The treatment is available to those who meet these criteria. For women undergoing premature menopause, MHT can be considered as a means to protect bone health, especially if initiated before menopause or if accelerated bone loss is documented soon after menopause. Such decisions should be made after evaluating individual risk factors and benefits.

Decoding the mechanism of Eleutheroside E in treating osteoporosis via network pharmacological analysis and molecular docking of osteoclast-related genes and gut microbiota.

Eleutheroside E (EE) is an anti-inflammatory natural compound derived from the edible medicinal herb Acanthopanax senticosus. This study aims to investigate the underlying mechanism of the anti-osteoporosis action of EE through network pharmacology, molecular docking and gut microbiota. Network pharmacology was used to explore the potential core targets and main pathways mediated by EE in osteoporosis (OP) treatment. Molecular docking was exploited to investigate the interactions between the active anti-OP compounds in EE and the potential downstream targets. Following the multi-approach bioinformatics analysis, ovariectomy (OVX) model was also established to investigate the in vivo anti-OP effects of EE. The top 10 core targets in PPI network were TP53, AKT1, JUN, CTNNB1, STAT3, HIF1A, EP300, CREB1, IL1B and ESR1. Molecular docking results that the binding energy of target proteins and the active compounds was approximately between -5.0 and -7.0 kcal/mol, which EE has the lowest docking binding energy with HIF1A. Enrichment analysis of GO and KEGG pathways of target proteins indicated that EE treatment could potentially alter numerous biological processes and cellular pathways. In vivo experiments demonstrated the protective effect of EE treatment against accelerated bone loss, where reduced serum levels of TRAP, CTX, TNF-α, LPS, and IL-6 and increased bone volume and serum levels of P1NP were observed in EE-treated mice. In addition, changes in gut microbiota were spotted by 16S rRNA gene sequencing, showing that EE treatment increased the relative abundance of Lactobacillus and decreased the relative abundance of Clostridiaceae. In summary, these findings suggested that the characteristics of multi-target and multi-pathway of EE against OP. In vivo, EE prevents the onset of OP by regulating gut microbiota and inflammatory response and is therefore a potential OP drug.

Mice Lacking PLAP-1/Asporin Show Alteration of Periodontal Ligament Structures and Acceleration of Bone Loss in Periodontitis.

Periodontal ligament-associated protein 1 (PLAP-1), also known as Asporin, is an extracellular matrix protein expressed in the periodontal ligament and plays a crucial role in periodontal tissue homeostasis. Our previous research demonstrated that PLAP-1 may inhibit TLR2/4-mediated inflammatory responses, thereby exerting a protective function against periodontitis. However, the precise roles of PLAP-1 in the periodontal ligament (PDL) and its relationship to periodontitis have not been fully explored. In this study, we employed PLAP-1 knockout mice to investigate its roles and contributions to PDL tissue and function in a ligature-induced periodontitis model. Mandibular bone samples were collected from 10-week-old male C57BL/6 (WT) and PLAP-1 knockout (KO) mice. These samples were analyzed through micro-computed tomography (μCT) scanning, hematoxylin and eosin (HE) staining, picrosirius red staining, and fluorescence immunostaining using antibodies targeting extracellular matrix proteins. Additionally, the structure of the PDL collagen fibrils was examined using transmission electron microscopy (TEM). We also conducted tooth extraction and ligature-induced periodontitis models using both wild-type and PLAP-1 KO mice. PLAP-1 KO mice did not exhibit any changes in alveolar bone resorption up to the age of 10 weeks, but they did display an enlarged PDL space, as confirmed by μCT and histological analyses. Fluorescence immunostaining revealed increased expression of extracellular matrix proteins, including Col3, BGN, and DCN, in the PDL tissues of PLAP-1 KO mice. TEM analysis demonstrated an increase in collagen diameter within the PDL of PLAP-1 KO mice. In line with these findings, the maximum stress required for tooth extraction was significantly lower in PLAP-1 KO mice in the tooth extraction model compared to WT mice (13.89 N ± 1.34 and 16.51 N ± 1.31, respectively). In the ligature-induced periodontitis model, PLAP-1 knockout resulted in highly severe alveolar bone resorption, with a higher number of collagen fiber bundle tears and significantly more osteoclasts in the periodontium. Our results demonstrate that mice lacking PLAP-1/Asporin show alteration of periodontal ligament structures and acceleration of bone loss in periodontitis. This underscores the significant role of PLAP-1 in maintaining collagen fibrils in the PDL and suggests the potential of PLAP-1 as a therapeutic target for periodontal diseases.

Herbal Remedies for Osteoporosis

Osteoporosis is a widespread concern that poses significant health risks. In the past, it was commonly thought that women would naturally undergo this condition as they age, especially during menopause when hormonal imbalances heighten the risk. Osteoporotic fractures affect approximately one in three women and one in five men over the age of 50 during their lifetimes. The mature skeleton constantly undergoes a remodelling process that involves both bone formation and resorption. However, when bone resorption exceeds bone growth, osteoporosis develops. Both men and women need to prioritize their bone health throughout their lives. Addressing factors that impact bone health at every stage becomes crucial in preventing osteoporosis. To combat the rising incidence of osteoporotic fractures, it is crucial to implement effective preventive measures aimed at maximizing peak bone density, limiting accelerated bone loss, and reducing the risk of falls. Present therapy goals primarily focus on stopping further bone loss and fractures, preserving bone mass, and utilizing medications like bisphosphonates, Selective Estrogen Receptor Modulators (SERMs), anabolic steroids, strontium, and Hormonal Replacement Therapy (HRT). However, it’s worth noting that some of these treatments, such as HRT, bisphosphonates, SERMs, and anabolic steroids, may have negative side effects. As a result, there is an urgent need to identify effective, affordable, natural, and less harmful compounds to manage osteopenia/osteoporosis effectively. The search for safer alternatives is crucial in combating this condition and promoting better bone health.

Effectiveness of anthocyanin-rich foods on bone remodeling biomarkers of middle-aged and older adults at risk of osteoporosis: a systematic review, meta-analysis, and meta-regression.

Current osteoporosis pharmacological treatment has undesirable side effects. There is increasing focus on naturally derived food substances that contain phytonutrients with antioxidant effects in promoting health and regulating immune response. This review aims to systematically evaluate the effectiveness of anthocyanin-rich foods on bone remodeling biomarkers in middle-aged and older adults (≥40 y old) at risk of osteoporosis. Randomized controlled trials were searched on 8 bibliographic databases of PubMed, Embase, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Food Science and Technology Abstracts, Cochrane Library, and ProQuest. Thirteen studies were included in the meta-analysis. Receptor activator of nuclear factor kappa-B ligand (RANKL) is exhibited from osteoblastic cells that gathered osteoclasts to bone sites for bone resorption, accelerating bone loss. Anthocyanin-rich food consumption showed statistically nonsignificant effects, with no substantial heterogeneity on bone remodeling biomarkers. However, there was a significant increase in lumbar spine L1-L4 bone mineral density. Mild-to-small effects were seen to largely favor the consumption of anthocyanin-rich foods. Berries (d = -0.44) have a larger effect size of RANKL than plums (d = 0.18), with statistically significant subgroup differences. Random-effects meta-regression found body mass index, total attrition rate, total energy, and dietary carbohydrate and fat intake were significant covariates for the effect size of RANKL. All outcomes had low certainty of evidence. Anthocyanin-rich foods may improve bone health in middle-aged and older adults at risk of osteoporosis. This review contributes to the growing interest in nutrient-rich foods as a low-cost and modifiable alternative to promote human health and reduce disease burden. Future high-quality studies with larger sample sizes and longer treatment durations are required to fully understand the effect of anthocyanin-rich foods on bone health. PROSPERO registration no. CRD42022367136.

Abstract P180: Hypertension-linked Immune Activation Regulates Osteoclastogenesis

Osteoporosis is an age-related disease affecting 18% of adults. Hypertension is associated with increased risk for fragility fracture and accelerated bone loss in adults. We hypothesized that experimental hypertension would induce osteoporosis and examined the mechanisms involved. We used two preclinical models in 12-week-old male C57Bl/6J mice: angiotensin (ang) II infusion (490 ng/kg/min) and deoxycorticosterone acetate (DOCA)-salt. After 6 weeks of ang II or 3 weeks of DOCA-salt, the left femur and sixth lumbar vertebral body were studied. Mechanical testing showed that ang II reduced femoral ultimate strength (170.7±4.794 vs 157.3±3.670 MPa, p=0.0325; 154.1±7.403 vs. 119.9±4.375 MPa, p=0.0026) and peak moment (39.09±1.660 vs. 32.77±0.9380 Newton millimeters (Nmm), p=0.0018; 29.15±1.291 vs 19.58±1.308 Nmm, p=0.0004) with cortical and trabecular bone loss compared to controls. μCT showed that hypertension reduced vertebral body bone volume fraction (30.1±1.41 vs 25.1±0.992 %, p=0.0068; 25.9±2.03 vs 18.5±1.29 %, p=0.0119) and trabecular thickness (62±1.6 vs 57±1.4 μm, p=0.0105; 60±2.1 vs 51 ±1.6 μm, p=0.0069). Flow cytometry of bone marrow from ang II-treated mice revealed that CD4+ T cells and γδ T cells produce increased IL-17A which is known to induce osteoclastogenesis. Colony stimulating factor-1 (CSF1) is also known to stimulate osteoclast formation. Using in situ hybridization, we observed increased CSF1 mRNA in endothelial cells (ECs) of transcortical arterioles of hypertensive mice. Subsequent studies of cultured bone marrow derived ECs showed that CSF1 mRNA expression increased with 0% and 10% compared to 5% stretch. 5% stretch treated with endothelial nitric oxide synthase inhibitor, L-NAME, increased expression comparable to 0% and 10%, indicating that nitric oxide inhibits CSF1 production. Thus, T-cell activation and nitric oxide-dependent EC dysfunction in hypertension may skew the bone marrow to favor osteoclastogenesis, leading to bone loss. Understanding this mechanism will elucidate novel pharmacological targets to mitigate hypertension-induced bone loss.