Can Probiotic Supplementation Improve Bone Mineral Density in Postmenopausal Women? A Systematic Review

Can Probiotic Supplementation Improve Bone Mineral Density in Postmenopausal Women? 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A Systematic Review Wenbin Sun, Dehong Chen, Jun Liu, Yunan Chen, Zhaoyan Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8411072/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Postmenopausal women face a high risk of osteoporosis, often necessitating long-term management strategies beyond conventional pharmacological treatments. The emerging "gut-bone axis" theory suggests that gut microbiota significantly influences bone metabolism, positioning probiotic supplementation as a potential novel intervention for bone health. Aim: This systematic review aims to evaluate the effects of probiotic supplementation on total hip and lumbar spine bone mineral density (BMD) in postmenopausal women. Methods: We searched PubMed, Web of Science, and the Cochrane Library databases for relevant randomized controlled trials (RCTs) from their inception to November 2025. Study quality was assessed using the Cochrane risk of bias tool. Data were pooled using standardized mean differences (SMD) with 95% confidence intervals (CIs) in a random-effects model, and heterogeneity was quantified using the I² statistic. Summary: Four RCTs involving 461 postmenopausal women were included. The pooled analysis showed a non-significant positive trend for both total hip BMD (SMD = 0.60, 95% CI: -0.17 to 1.38) and lumbar spine BMD (SMD = 0.48, 95% CI: -0.03 to 1.00), with considerable heterogeneity (I² = 95% and 89%, respectively). Current evidence suggests a potential beneficial effect of probiotics on BMD, likely mediated through gut microbiota regulation, estrogen metabolism, and inflammatory modulation. However, the conclusions are limited by the small number of studies, high heterogeneity, and varying intervention protocols. Future large-scale, long-term RCTs with standardized protocols are warranted to confirm these findings and elucidate optimal probiotic strategies. Probiotics Postmenopausal women Osteoporosis Systematic review Gut-bone axis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction 1.1 Research Background Osteoporosis (OP) is a common metabolic bone disorder characterized by reduced bone mass and impaired bone microarchitecture, leading to increased bone fragility and elevated fracture risk [ 1 ]. This disease is categorized into primary and secondary types: primary OP arises from aging and estrogen deficiency, while secondary OP results from underlying diseases or medications [ 2 ]. Postmenopausal women face heightened OP risk due to aging and hormonal imbalances disrupting the equilibrium between bone formation and resorption. Among primary osteoporosis, postmenopausal osteoporosis (PMOP) is the most prevalent form [ 3 ]. Current clinical management of PMOP primarily relies on bisphosphonates and estrogen replacement therapy. However, long-term use of these medications may induce adverse effects such as poor fracture outcomes and increased cancer risk [ 4 ][ 5 ]. Therefore, exploring safe, effective, and well-tolerated supplementary interventions holds significant clinical importance. In recent years, the emergence of the “gut-bone axis” theory has opened new perspectives for osteoporosis prevention and treatment [ 6 ]. As the largest microbial ecosystem in the human body, alterations in the structure and function of the gut microbiota are closely linked to skeletal health [ 7 ]. Probiotics, as key mediators regulating the gut microbiota, may profoundly influence bone metabolism through pathways including improving the intestinal microenvironment, modulating immune-inflammatory responses, and affecting nutrient absorption and hormone metabolism [ 8 ][ 9 ]. Existing research suggests probiotic supplementation may hold potential for enhancing bone density and improving bone metabolism [ 10 ], but systematic evidence-based medical data regarding its effects in postmenopausal women remains lacking. 1.2 Research Objectives This study aims to synthesize existing randomized controlled trial evidence to examine the effects of probiotic supplementation on lumbar spine and total hip bone mineral density in postmenopausal women, providing scientific basis for clinical interventions and future research on PMOP. 1.3 Research Significance Further elucidate the mechanism of the “gut-bone axis” in postmenopausal women, enriching the theoretical framework of osteoporosis pathogenesis. To offer a potentially safe, effective, and cost-effective supplemental intervention for postmenopausal women with osteoporosis, providing evidence-based support for clinical decision-making. 2. Methods 2.1 Literature Search Strategy Databases including PubMed, Web of Science, and Cochrane Library were searched from their inception to November 2025. Search terms combined subject headings with free-text keywords, including “probiotics,” “postmenopausal women,” “osteoporosis,” “bone mineral density,” “randomized controlled trial,” and “gastrointestinal microbiomes.” References from included studies were manually searched to supplement potentially overlooked literature. 2.2 Inclusion and Exclusion Criteria for Literature Inclusion and exclusion criteria were strictly defined according to the PICOS framework (P: population; I: intervention; C: comparison; O: outcome; S: study design) (Table 1). Table 1.PICOS framework for the study Population (P) postmenopausal women Intervention (I) probiotics Comparison (C) •Placebo intervention •Sham intervention Outcomes (O) •Lumbar spine BMD •Total hip BMD •Gut microbiota •Adverse events Study Design(S) RCT Inclusion Criteria: •Study type: Randomized controlled trial (RCT); •Study population: Postmenopausal women; •Intervention: Probiotic supplementation (with specified strains, dosage, and duration); •control group: placebo or standard care; •Outcome measures: Changes in total hip or lumbar spine bone mineral density (BMD). Exclusion Criteria: •Non-RCT studies (e.g., cohort studies, case-control studies); •Inclusion of male subjects or premenopausal women; •Absence of bone mineral density data or inability to extract such data; •Duplicate publications; •Interventions combining probiotics with other osteoporosis medications, precluding separate analysis of probiotic effects. 2.3 Literature Screening and Data Extraction Two researchers independently screened titles, abstracts, and full texts, cross-verifying results. Disagreements were resolved through discussion or third-party consultation. 2.4 Risk of Bias Assessment The Cochrane Risk of Bias tool was used to assess study quality across seven domains: 1. Random sequence generation (selection bias); 2. Allocation concealment (selection bias); 3. Blinding of participants and personnel (performance bias); 4. Blinding of outcome assessment (detection bias); 5. Completeness of outcome data (attrition bias); 6. Selective reporting (reporting bias); 7. Other biases. Risk levels for each domain are categorized as low risk (green), unclear (yellow), or high risk (red). 2.5 Statistical Analysis Literature quality assessment was conducted using Revman software, with analysis performed in R software. Standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect size measures. Heterogeneity was assessed using the I² statistic. A random-effects model was applied if high heterogeneity was present; otherwise, a fixed-effects model was used. 3. Results 3.1 Literature Search Findings A systematic search of PubMed, Web of Science, and the Cochrane Library yielded 617 initial records. After removing duplicates, 221 articles proceeded to screening. Initial title and abstract screening excluded 159 articles that did not meet the criteria. Full-text reviews of the remaining 62 studies led to the exclusion of 58 studies, primarily due to: lack of detailed data (n = 27), discussion of unrelated topics (n = 19), and non-compliance with study design or exposure criteria (n = 12). Ultimately, four randomized controlled trials (RCTs) were included in this systematic review. The study inclusion flowchart is shown in Fig. 1 . 3.2 Basic Characteristics of Included Studies The four included studies involved a total of 461 postmenopausal female participants, comprising 235 in the treatment group and 226 in the control group. Intervention durations ranged from 12 weeks to 12 months, with probiotic strains including common species such as Lactobacillus (e.g., Lactobacillus acidophilus, Lactobacillus casei) and Bifidobacterium (e.g., Bifidobacterium lactis). Specific characteristics are summarized in Table 2 . Table 2 Summary of studies Author, study design Country Study Type of intervention Subjects Outcome measures Year duration Trial Group Control Group Trial Group Control Group Nillsson,2018 11 RCT Sweden 12 months Freeze-dried L. reuteri 6475 in Consisted of 45 45 BMD doses of 5 × 109 (CFU) mixed maltodextrin powder BALP, CRP along with maltodextrin TNF-α,a, NTx powder taken twice daily, Adverse events yielding a total daily dose of 1 × 1010 CFU day_1 Takimoto,2018 12 RCT Japan 24 weeks Dried soybeans fermented Tablets containing 38 38 BMD, TRACP-5b using a pre-culture prepared dextrin instead of the BAP, PTH from soybean oil residue soybean fermentation Gut microbiota analysis inoculated with Bacillus extract subtilis (C-3102) Han,2022 13 RCT Korea 6 months Probiotics capsule ( L. Capsule 30 28 BMD, CTX + OC, BALP fermentum SRK414, microcrystalline ALP, 25(OH)D 4.0 × 109 CFU) cellulose) twice a day Gut microbiota concentration Adverse events Schott,2025 14 RCT Australia 6/12 months SBD111 synbiotic medical food, Capsule Consisted of 122/115 115/105 BMD,CTX vitaminD(500 IU) maltodextrin powder BALP,CRP vitaminD(500 IU) TNF-α,IL-1β RANKL,IL-4 Adverse events 3.3 Risk of Bias Assessment Risk of bias assessments for the included studies are presented in Fig. 2 . 3.4 Analysis Results 3.4.1 Changes in Lumbar Spine BMD A meta-analysis was conducted on four randomized controlled trials evaluating changes in lumbar spine bone mineral density (BMD). Results from each study are presented in Fig. 3 . The analysis revealed conflicting findings across studies. Two studies (Nilsson, 2018[ 11 ]; Takimoto, 2018[ 12 ]) demonstrated positive effects of the interventions (SMDs of 0.57 and 1.96, respectively), while the remaining studies (Han, 2022[ 13 ]; Schott, 2025[ 14 ]) observed no effect (all SMD 95% confidence intervals included zero). High heterogeneity existed among studies (I² = 89%, τ² = 0.3005, p < 0.0001). 3.4.2 Changes in Total Hip BMD This study conducted a meta-analysis of randomized controlled trials evaluating changes in total hip bone mineral density (BMD). Results from individual studies are shown in Fig. 4 . Analysis revealed divergent outcomes across studies. Takimoto 2018 [ 12 ] reported a positive effect (SMD = 2.91), whereas Han 2022 [ 13 ] demonstrated a negative effect (SMD = -2.91). The direction and magnitude of results from other studies were also inconsistent. Extremely high heterogeneity existed between studies (I² = 95%, τ² = 0.7195, p < 0.0001). The pooled effect size from the random-effects model was not statistically significant (SMD = 0.60, 95% CI: -0.17 to 1.38). 4. Discussion 4.1 Effects of Probiotics on Bone Mineral Density in Postmenopausal Women Our findings indicate that while the pooled effect size for probiotic supplementation on changes in total hip and lumbar spine BMD was positive, the difference was not statistically significant due to high heterogeneity. This partially aligns with previous meta-analysis results in postmenopausal women. 4.2 Analysis of Sources of Heterogeneity The high heterogeneity observed in this study may stem from the following sources: Differences in study population characteristics: Included postmenopausal women varied in age, duration since menopause, baseline bone density, and BMI. Variations in probiotic intervention protocols: Differences existed in probiotic strains (e.g., Lactobacillus spp., Bifidobacterium spp.), dosage, intervention duration, and whether prebiotics were co-administered. Different strains may influence bone health through distinct metabolic pathways, while varying intervention durations could also lead to differences in effect sizes. Differences in outcome measurement methods: Although dual-energy X-ray absorptiometry (DXA) was used to measure bone density across studies, subtle variations in imaging equipment, site selection, and operational standards may have contributed to heterogeneity. 4.3 Exploring Mechanisms: The Unique Association Between the Gut-Bone Axis and Postmenopausal Women In postmenopausal women, the mechanisms underlying the gut-bone axis may be more complex, as illustrated in Fig. 5 . 4.3.1 Bidirectional Regulation Between Gut Microbiota and Estrogen Metabolism Postmenopausal women experience a sharp decline in estrogen levels, leading to alterations in gut microbiota composition. Beneficial bacteria such as Bifidobacteria and Lactobacillus decrease in abundance, while potentially pathogenic bacteria increase [ 15 ][ 16 ]. Concurrently, gut microbiota can influence estrogen levels through metabolic processes [ 17 ]. 4.3.2 Regulation of Gut Microbiota and Inflammatory Responses Declining estrogen levels in postmenopausal women exacerbate inflammatory responses. Chronic low-grade inflammation promotes osteoclast activity and accelerates bone loss [ 18 ]. Probiotics can modulate gut microbiota to reduce production of pro-inflammatory factors (e.g., IL-6, TNF-α) while increasing secretion of anti-inflammatory factors (e.g., IL-10), thereby inhibiting inflammation-mediated bone resorption [ 19 ][ 20 ]. 4.3.3 Improvement of Gut Microbiota and Nutrient Absorption Probiotics enhance intestinal barrier function, promoting absorption of bone-health-related nutrients like calcium and vitamin D. Vitamin D deficiency is common among postmenopausal women, and probiotics may increase vitamin D bioavailability by modulating gut microbiota, thereby enhancing calcium absorption [ 21 ]. 4.4 Study Limitations Limited number of included studies: Only four RCTs were included, with relatively small sample sizes potentially affecting statistical power. Variable study quality: Some studies carried risks of allocation concealment and blinding implementation, potentially introducing bias. Lack of Subgroup Analysis by Probiotic Strain and Dose: Due to significant variations in intervention protocols across included studies, detailed subgroup analyses were not feasible, making it difficult to determine the optimal probiotic strain or dosage. Short Follow-up Duration: Most studies had follow-up periods of less than 12 months, lacking long-term data to assess the sustained efficacy and safety of probiotics. 5. Conclusions and Outlook 5.1 Conclusions Current evidence suggests that probiotic supplementation may positively influence bone mineral density in postmenopausal women with osteoporosis. Its mechanisms of action are likely closely related to regulating gut microbiota, improving estrogen metabolism, suppressing inflammatory responses, and promoting nutrient absorption. However, due to the limited number of included studies and high heterogeneity, these conclusions require further validation. 5.2 Future Directions Conduct large-scale, multicenter, long-term follow-up randomized controlled trials (RCTs) with standardized intervention protocols (including probiotic strains, dosage, and intervention duration) and outcome assessment criteria to enhance study reliability and comparability. Further explore the specific molecular mechanisms of the gut-bone axis in postmenopausal women to clarify the target sites of different probiotic strains. Investigate the combined effects of probiotics with other osteoporosis therapies (such as bisphosphonates and estrogen replacement therapy), evaluating their synergistic effects and safety. Declarations Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements: We would like to acknowledge all participants enrolled in this study. Declaration of generative AI and AI-assisted technologies in the manuscript preparation process During preparation of this work, we used DeepSeek in order to help with writing in English. After using this service, we reviewed and edited the content as needed and take full responsibility for the content of the published article. References Compston, J. E., McClung, M. R. & Leslie, W. D. Osteoporosis. Lancet 393 , 364-376 (2019). https://doi.org/10.1016/s0140-6736(18)32112-3 Tannenbaum, C. et al. 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Butyrate's role in human health and the current progress towards its clinical application to treat gastrointestinal disease. Clin Nutr 42 , 61-75 (2023). https://doi.org/10.1016/j.clnu.2022.10.024 White, J. H. Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity. Nutrients 14 (2022). https://doi.org/10.3390/nu14020284 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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07:07:22","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33752,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/ec899afa92d348f7ba37df0c.png"},{"id":98853164,"identity":"cc6859e9-6224-47f0-89a5-1cbbd21b257e","added_by":"auto","created_at":"2025-12-23 07:07:21","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70293,"visible":true,"origin":"","legend":"","description":"","filename":"rs84110720structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/c740ee45434affd8c8ed051f.xml"},{"id":98853170,"identity":"4786ea7f-6cfa-4906-8038-3bb380e2c245","added_by":"auto","created_at":"2025-12-23 07:07:22","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":81386,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/f6deacb6c26f97eb795e9b3d.html"},{"id":98853151,"identity":"d64a580c-dc11-415b-a5bf-b4952fd82db9","added_by":"auto","created_at":"2025-12-23 07:07:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":63341,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of study selection for inclusion in the systematic review\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/d3cbfc31f3ff5399c769abbe.png"},{"id":98853152,"identity":"563181e5-00a2-475a-8691-8eadc527b60b","added_by":"auto","created_at":"2025-12-23 07:07:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":118005,"visible":true,"origin":"","legend":"\u003cp\u003eRisk assessment scale of studies.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/ab8a7129c1e3026e98c41652.png"},{"id":99308356,"identity":"dd37a0e5-f190-4633-a48d-844166e80b60","added_by":"auto","created_at":"2025-12-31 16:08:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":134587,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of probiotics supplements on lumbar spine BMD\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/2c139fdda849abdff832aacd.png"},{"id":98853156,"identity":"f2056c81-aa92-4bfc-9fad-643afaac8aae","added_by":"auto","created_at":"2025-12-23 07:07:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":201206,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of probiotics supplements on hip BMD\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/10e6fb1a0a963bcbaf767720.png"},{"id":98853163,"identity":"c38e2240-67e4-4a8d-b6dc-c7e33eddbd0f","added_by":"auto","created_at":"2025-12-23 07:07:21","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":129480,"visible":true,"origin":"","legend":"\u003cp\u003eGut-bone axis Schematic Diagram\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/14faeb304afc4cf4f1b590f0.png"},{"id":99322728,"identity":"de9e4886-1584-4cdf-a697-54cf0418482c","added_by":"auto","created_at":"2025-12-31 16:44:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1581313,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8411072/v1/49b48646-f0aa-416f-927d-7a2b115fdaea.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCan Probiotic Supplementation Improve Bone Mineral Density in Postmenopausal Women? A Systematic Review\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1 Research Background\u003c/h2\u003e \u003cp\u003eOsteoporosis (OP) is a common metabolic bone disorder characterized by reduced bone mass and impaired bone microarchitecture, leading to increased bone fragility and elevated fracture risk [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This disease is categorized into primary and secondary types: primary OP arises from aging and estrogen deficiency, while secondary OP results from underlying diseases or medications [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Postmenopausal women face heightened OP risk due to aging and hormonal imbalances disrupting the equilibrium between bone formation and resorption. Among primary osteoporosis, postmenopausal osteoporosis (PMOP) is the most prevalent form [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent clinical management of PMOP primarily relies on bisphosphonates and estrogen replacement therapy. However, long-term use of these medications may induce adverse effects such as poor fracture outcomes and increased cancer risk [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, exploring safe, effective, and well-tolerated supplementary interventions holds significant clinical importance.\u003c/p\u003e \u003cp\u003eIn recent years, the emergence of the \u0026ldquo;gut-bone axis\u0026rdquo; theory has opened new perspectives for osteoporosis prevention and treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. As the largest microbial ecosystem in the human body, alterations in the structure and function of the gut microbiota are closely linked to skeletal health [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Probiotics, as key mediators regulating the gut microbiota, may profoundly influence bone metabolism through pathways including improving the intestinal microenvironment, modulating immune-inflammatory responses, and affecting nutrient absorption and hormone metabolism [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Existing research suggests probiotic supplementation may hold potential for enhancing bone density and improving bone metabolism [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], but systematic evidence-based medical data regarding its effects in postmenopausal women remains lacking.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Research Objectives\u003c/h2\u003e \u003cp\u003eThis study aims to synthesize existing randomized controlled trial evidence to examine the effects of probiotic supplementation on lumbar spine and total hip bone mineral density in postmenopausal women, providing scientific basis for clinical interventions and future research on PMOP.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.3 Research Significance\u003c/h2\u003e \u003cp\u003eFurther elucidate the mechanism of the \u0026ldquo;gut-bone axis\u0026rdquo; in postmenopausal women, enriching the theoretical framework of osteoporosis pathogenesis. To offer a potentially safe, effective, and cost-effective supplemental intervention for postmenopausal women with osteoporosis, providing evidence-based support for clinical decision-making.\u003c/p\u003e \u003c/div\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Literature Search Strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatabases including PubMed, Web of Science, and Cochrane Library were searched from their inception to November 2025. Search terms combined subject headings with free-text keywords, including \u0026ldquo;probiotics,\u0026rdquo; \u0026ldquo;postmenopausal women,\u0026rdquo; \u0026ldquo;osteoporosis,\u0026rdquo; \u0026ldquo;bone mineral density,\u0026rdquo; \u0026ldquo;randomized controlled trial,\u0026rdquo; and \u0026ldquo;gastrointestinal microbiomes.\u0026rdquo; References from included studies were manually searched to supplement potentially overlooked literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Inclusion and Exclusion Criteria for Literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion and exclusion criteria were strictly defined according to the PICOS framework (P: population; I: intervention; C: comparison; O: outcome; S: study design) (Table 1).\u003c/p\u003e\n\u003cp\u003eTable 1.PICOS framework for the study\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePopulation (P)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003epostmenopausal women\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention (I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eprobiotics\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eComparison (C)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026bull;Placebo intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026bull;Sham intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOutcomes (O)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026bull;Lumbar spine BMD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026bull;Total hip BMD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026bull;Gut microbiota\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026bull;Adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStudy Design(S)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInclusion Criteria:\u003c/p\u003e\n\u003cp\u003e\u0026bull;Study type: Randomized controlled trial (RCT);\u003c/p\u003e\n\u003cp\u003e\u0026bull;Study population: Postmenopausal women;\u003c/p\u003e\n\u003cp\u003e\u0026bull;Intervention: Probiotic supplementation (with specified strains, dosage, and duration);\u0026nbsp;\u0026bull;control group: placebo or standard care;\u003c/p\u003e\n\u003cp\u003e\u0026bull;Outcome measures: Changes in total hip or lumbar spine bone mineral density (BMD).\u003c/p\u003e\n\u003cp\u003eExclusion Criteria:\u003c/p\u003e\n\u003cp\u003e\u0026bull;Non-RCT studies (e.g., cohort studies, case-control studies);\u003c/p\u003e\n\u003cp\u003e\u0026bull;Inclusion of male subjects or premenopausal women;\u003c/p\u003e\n\u003cp\u003e\u0026bull;Absence of bone mineral density data or inability to extract such data;\u003c/p\u003e\n\u003cp\u003e\u0026bull;Duplicate publications;\u003c/p\u003e\n\u003cp\u003e\u0026bull;Interventions combining probiotics with other osteoporosis medications, precluding separate analysis of probiotic effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Literature Screening and Data Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo researchers independently screened titles, abstracts, and full texts, cross-verifying results. Disagreements were resolved through discussion or third-party consultation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Risk of Bias Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Cochrane Risk of Bias tool was used to assess study quality across seven domains:\u003c/p\u003e\n\u003cp\u003e1. Random sequence generation (selection bias);\u003c/p\u003e\n\u003cp\u003e2. Allocation concealment (selection bias);\u003c/p\u003e\n\u003cp\u003e3. Blinding of participants and personnel (performance bias);\u003c/p\u003e\n\u003cp\u003e4. Blinding of outcome assessment (detection bias);\u003c/p\u003e\n\u003cp\u003e5. Completeness of outcome data (attrition bias);\u003c/p\u003e\n\u003cp\u003e6. Selective reporting (reporting bias);\u003c/p\u003e\n\u003cp\u003e7. Other biases.\u003c/p\u003e\n\u003cp\u003eRisk levels for each domain are categorized as low risk (green), unclear (yellow), or high risk (red).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiterature quality assessment was conducted using Revman software, with analysis performed in R software. Standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect size measures. Heterogeneity was assessed using the I\u0026sup2; statistic. A random-effects model was applied if high heterogeneity was present; otherwise, a fixed-effects model was used.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Literature Search Findings\u003c/h2\u003e \u003cp\u003eA systematic search of PubMed, Web of Science, and the Cochrane Library yielded 617 initial records. After removing duplicates, 221 articles proceeded to screening. Initial title and abstract screening excluded 159 articles that did not meet the criteria. Full-text reviews of the remaining 62 studies led to the exclusion of 58 studies, primarily due to: lack of detailed data (n\u0026thinsp;=\u0026thinsp;27), discussion of unrelated topics (n\u0026thinsp;=\u0026thinsp;19), and non-compliance with study design or exposure criteria (n\u0026thinsp;=\u0026thinsp;12). Ultimately, four randomized controlled trials (RCTs) were included in this systematic review. The study inclusion flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Basic Characteristics of Included Studies\u003c/h2\u003e \u003cp\u003eThe four included studies involved a total of 461 postmenopausal female participants, comprising 235 in the treatment group and 226 in the control group. Intervention durations ranged from 12 weeks to 12 months, with probiotic strains including common species such as Lactobacillus (e.g., Lactobacillus acidophilus, Lactobacillus casei) and Bifidobacterium (e.g., Bifidobacterium lactis). Specific characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor,\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003estudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eType of intervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eSubjects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOutcome measures\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eduration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTrial Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eControl Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTrial Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eControl Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNillsson,2018\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSweden\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFreeze-dried \u003cem\u003eL. reuteri\u003c/em\u003e 6475 in\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eConsisted of\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBMD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003edoses of 5 \u0026times; 109 (CFU) mixed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emaltodextrin powder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBALP, CRP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ealong with maltodextrin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTNF-α,a, NTx\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003epowder taken twice daily,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eyielding a total daily dose of\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 \u0026times; 1010 CFU day_1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTakimoto,2018\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDried soybeans fermented\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTablets containing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBMD, TRACP-5b\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eusing a pre-culture prepared\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003edextrin instead of the\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBAP, PTH\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003efrom soybean oil residue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003esoybean fermentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGut microbiota analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einoculated with Bacillus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eextract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esubtilis (C-3102)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHan,2022\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eProbiotics capsule (\u003cem\u003eL.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCapsule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBMD, CTX\u0026thinsp;\u003cb\u003e+\u003c/b\u003e\u0026thinsp;OC, BALP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003efermentum\u003c/em\u003e SRK414,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emicrocrystalline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eALP, 25(OH)D\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.0 \u0026times; 109 CFU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ecellulose) twice a day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGut microbiota\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003econcentration\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchott,2025\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSBD111 synbiotic medical food,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCapsule Consisted of\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e122/115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e115/105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBMD,CTX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003evitaminD(500 IU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emaltodextrin powder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBALP,CRP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003evitaminD(500 IU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTNF-α,IL-1β\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eRANKL,IL-4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of Bias Assessment\u003c/h2\u003e \u003cp\u003eRisk of bias assessments for the included studies are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Analysis Results\u003c/h2\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1 Changes in Lumbar Spine BMD\u003c/h2\u003e \u003cp\u003eA meta-analysis was conducted on four randomized controlled trials evaluating changes in lumbar spine bone mineral density (BMD). Results from each study are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The analysis revealed conflicting findings across studies. Two studies (Nilsson, 2018[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; Takimoto, 2018[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]) demonstrated positive effects of the interventions (SMDs of 0.57 and 1.96, respectively), while the remaining studies (Han, 2022[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]; Schott, 2025[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]) observed no effect (all SMD 95% confidence intervals included zero). High heterogeneity existed among studies (I\u0026sup2; = 89%, τ\u0026sup2; = 0.3005, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2 Changes in Total Hip BMD\u003c/h2\u003e \u003cp\u003eThis study conducted a meta-analysis of randomized controlled trials evaluating changes in total hip bone mineral density (BMD). Results from individual studies are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Analysis revealed divergent outcomes across studies. Takimoto 2018 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] reported a positive effect (SMD\u0026thinsp;=\u0026thinsp;2.91), whereas Han 2022 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] demonstrated a negative effect (SMD = -2.91). The direction and magnitude of results from other studies were also inconsistent. Extremely high heterogeneity existed between studies (I\u0026sup2; = 95%, τ\u0026sup2; = 0.7195, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The pooled effect size from the random-effects model was not statistically significant (SMD\u0026thinsp;=\u0026thinsp;0.60, 95% CI: -0.17 to 1.38).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Effects of Probiotics on Bone Mineral Density in Postmenopausal Women\u003c/h2\u003e \u003cp\u003eOur findings indicate that while the pooled effect size for probiotic supplementation on changes in total hip and lumbar spine BMD was positive, the difference was not statistically significant due to high heterogeneity. This partially aligns with previous meta-analysis results in postmenopausal women.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Analysis of Sources of Heterogeneity\u003c/h2\u003e \u003cp\u003eThe high heterogeneity observed in this study may stem from the following sources:\u003c/p\u003e \u003cp\u003eDifferences in study population characteristics: Included postmenopausal women varied in age, duration since menopause, baseline bone density, and BMI.\u003c/p\u003e \u003cp\u003eVariations in probiotic intervention protocols: Differences existed in probiotic strains (e.g., Lactobacillus spp., Bifidobacterium spp.), dosage, intervention duration, and whether prebiotics were co-administered. Different strains may influence bone health through distinct metabolic pathways, while varying intervention durations could also lead to differences in effect sizes.\u003c/p\u003e \u003cp\u003eDifferences in outcome measurement methods: Although dual-energy X-ray absorptiometry (DXA) was used to measure bone density across studies, subtle variations in imaging equipment, site selection, and operational standards may have contributed to heterogeneity.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Exploring Mechanisms: The Unique Association Between the Gut-Bone Axis and Postmenopausal Women\u003c/h2\u003e \u003cp\u003eIn postmenopausal women, the mechanisms underlying the gut-bone axis may be more complex, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e4.3.1 Bidirectional Regulation Between Gut Microbiota and Estrogen Metabolism\u003c/h2\u003e \u003cp\u003ePostmenopausal women experience a sharp decline in estrogen levels, leading to alterations in gut microbiota composition. Beneficial bacteria such as Bifidobacteria and Lactobacillus decrease in abundance, while potentially pathogenic bacteria increase [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Concurrently, gut microbiota can influence estrogen levels through metabolic processes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e4.3.2 Regulation of Gut Microbiota and Inflammatory Responses\u003c/h2\u003e \u003cp\u003eDeclining estrogen levels in postmenopausal women exacerbate inflammatory responses. Chronic low-grade inflammation promotes osteoclast activity and accelerates bone loss [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Probiotics can modulate gut microbiota to reduce production of pro-inflammatory factors (e.g., IL-6, TNF-α) while increasing secretion of anti-inflammatory factors (e.g., IL-10), thereby inhibiting inflammation-mediated bone resorption [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e][\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e4.3.3 Improvement of Gut Microbiota and Nutrient Absorption\u003c/h2\u003e \u003cp\u003eProbiotics enhance intestinal barrier function, promoting absorption of bone-health-related nutrients like calcium and vitamin D. Vitamin D deficiency is common among postmenopausal women, and probiotics may increase vitamin D bioavailability by modulating gut microbiota, thereby enhancing calcium absorption [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Study Limitations\u003c/h2\u003e \u003cp\u003eLimited number of included studies: Only four RCTs were included, with relatively small sample sizes potentially affecting statistical power. Variable study quality: Some studies carried risks of allocation concealment and blinding implementation, potentially introducing bias. Lack of Subgroup Analysis by Probiotic Strain and Dose: Due to significant variations in intervention protocols across included studies, detailed subgroup analyses were not feasible, making it difficult to determine the optimal probiotic strain or dosage. Short Follow-up Duration: Most studies had follow-up periods of less than 12 months, lacking long-term data to assess the sustained efficacy and safety of probiotics.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions and Outlook","content":"\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003e5.1 Conclusions\u003c/h2\u003e \u003cp\u003eCurrent evidence suggests that probiotic supplementation may positively influence bone mineral density in postmenopausal women with osteoporosis. Its mechanisms of action are likely closely related to regulating gut microbiota, improving estrogen metabolism, suppressing inflammatory responses, and promoting nutrient absorption. However, due to the limited number of included studies and high heterogeneity, these conclusions require further validation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003e5.2 Future Directions\u003c/h2\u003e \u003cp\u003eConduct large-scale, multicenter, long-term follow-up randomized controlled trials (RCTs) with standardized intervention protocols (including probiotic strains, dosage, and intervention duration) and outcome assessment criteria to enhance study reliability and comparability. Further explore the specific molecular mechanisms of the gut-bone axis in postmenopausal women to clarify the target sites of different probiotic strains. Investigate the combined effects of probiotics with other osteoporosis therapies (such as bisphosphonates and estrogen replacement therapy), evaluating their synergistic effects and safety.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial\u0026nbsp;interests or personal\u0026nbsp;relationships that could have appeared to influence\u0026nbsp;the work reported in this paper.\u003c/p\u003e\n\u003cp\u003eAcknowledgements:\u0026nbsp;We would like to acknowledge all participants enrolled in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI and AI-assisted technologies in the manuscript preparation process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring preparation of this work, we used DeepSeek in order to help with writing in English. After using this service, we reviewed and edited the content as needed and take full responsibility for the content of the published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCompston, J. E., McClung, M. R. \u0026amp; Leslie, W. D. Osteoporosis. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e393\u003c/strong\u003e, 364-376 (2019). https://doi.org/10.1016/s0140-6736(18)32112-3\u003c/li\u003e\n\u003cli\u003eTannenbaum, C.\u003cem\u003e et al.\u003c/em\u003e Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e \u003cstrong\u003e87\u003c/strong\u003e, 4431-4437 (2002). https://doi.org/10.1210/jc.2002-020275\u003c/li\u003e\n\u003cli\u003eWalker, M. D. \u0026amp; Shane, E. 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Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases. \u003cem\u003eJ Neurogastroenterol Motil\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 201-212 (2016). https://doi.org/10.5056/jnm15146\u003c/li\u003e\n\u003cli\u003eRizzetto, L., Fava, F., Tuohy, K. M. \u0026amp; Selmi, C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex. \u003cem\u003eJ Autoimmun\u003c/em\u003e \u003cstrong\u003e92\u003c/strong\u003e, 12-34 (2018). https://doi.org/10.1016/j.jaut.2018.05.008\u003c/li\u003e\n\u003cli\u003eHodgkinson, K.\u003cem\u003e et al.\u003c/em\u003e Butyrate\u0026apos;s role in human health and the current progress towards its clinical application to treat gastrointestinal disease. \u003cem\u003eClin Nutr\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 61-75 (2023). https://doi.org/10.1016/j.clnu.2022.10.024\u003c/li\u003e\n\u003cli\u003eWhite, J. H. Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity. \u003cem\u003eNutrients\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e (2022). https://doi.org/10.3390/nu14020284\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Taizhou Enze Medical Center (Group) (Taizhou University Affiliated Enze Medical Center) ,School of Medicine, Taizhou University, Linhai, China","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Probiotics, Postmenopausal women, Osteoporosis, Systematic review, Gut-bone axis","lastPublishedDoi":"10.21203/rs.3.rs-8411072/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8411072/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Postmenopausal women face a high risk of osteoporosis, often necessitating long-term management strategies beyond conventional pharmacological treatments. The emerging \"gut-bone axis\" theory suggests that gut microbiota significantly influences bone metabolism, positioning probiotic supplementation as a potential novel intervention for bone health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e This systematic review aims to evaluate the effects of probiotic supplementation on total hip and lumbar spine bone mineral density (BMD) in postmenopausal women.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We searched PubMed, Web of Science, and the Cochrane Library databases for relevant randomized controlled trials (RCTs) from their inception to November 2025. Study quality was assessed using the Cochrane risk of bias tool. Data were pooled using standardized mean differences (SMD) with 95% confidence intervals (CIs) in a random-effects model, and heterogeneity was quantified using the I² statistic.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary:\u003c/strong\u003e Four RCTs involving 461 postmenopausal women were included. The pooled analysis showed a non-significant positive trend for both total hip BMD (SMD = 0.60, 95% CI: -0.17 to 1.38) and lumbar spine BMD (SMD = 0.48, 95% CI: -0.03 to 1.00), with considerable heterogeneity (I² = 95% and 89%, respectively). Current evidence suggests a potential beneficial effect of probiotics on BMD, likely mediated through gut microbiota regulation, estrogen metabolism, and inflammatory modulation. However, the conclusions are limited by the small number of studies, high heterogeneity, and varying intervention protocols. Future large-scale, long-term RCTs with standardized protocols are warranted to confirm these findings and elucidate optimal probiotic strategies.\u003c/p\u003e","manuscriptTitle":"Can Probiotic Supplementation Improve Bone Mineral Density in Postmenopausal Women? A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-23 07:07:16","doi":"10.21203/rs.3.rs-8411072/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"084496fe-a08c-46ed-a865-55ba6f2cf8b2","owner":[],"postedDate":"December 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-23T07:07:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-23 07:07:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8411072","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8411072","identity":"rs-8411072","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}