The impact of probiotics and synbiotics supplementation on bone health;an umbrella review of systematic reviews and meta-analysis

Abstract

Background

The effects of probiotics and synbiotics on bone health remain uncertain due to conflicting results across existing systematic reviews and meta-analyses (SRs/MAs).

Methods

PubMed/Medline, Cochrane, and Web of Science were searched through February 2025. SRs/MAs on probiotics or synbiotics for bone health were included. An umbrella review with meta-analysis of pooled effect sizes was conducted using random-effects models: Hedges’ g for bone mineral density (BMD) and muscle mass, and mean difference for muscle strength. Heterogeneity was assessed via I², and AMSTAR2 rated confidence. PROSPERO ID: CRD42025636002.

Results

Our initial search identified 930 articles (488 from PubMed/MEDLINE, 260 from Web of Science, and 182 from Cochrane). After removing duplicates and screening titles, abstracts, and full texts, sixteen systematic reviews and meta-analyses were included (with 3,245 participants), and only human studies were considered for meta-analysis. Most studies investigated Lactobacillus and Bifidobacterium strains as probiotics. Probiotics and synbiotics supplementation significantly improved BMD (Weighted mean difference (WMD) = 0.39, 95% Confidence interval (CI): 0.14, 0.63, p = 0.002), muscle mass (WMD = 0.46, 95% CI: 0.23, 0.68, p < 0.001), and muscle strength (WMD = 1.99, 95% CI: 0.42, 3.57, p = 0.013). Subgroup analyses identified BMD measurement site, number of studies, sample size, and gender as sources of heterogeneity. According to AMSTAR2, 11 reviews were rated as high confidence, one as moderate confidence, and four as low confidences.

Conclusion

Probiotic/synbiotic supplementation showed modest, statistically significant BMD benefits, but with substantial heterogeneity. Findings for muscle mass and strength were based on a few meta-analyses, showed high heterogeneity, and sensitivity analyses nullified significance. Current evidence does not support clinical recommendations for probiotics/synbiotics in bone health prevention.

Keywords

probiotics synbiotics bone health musculoskeletal disease osteoporosis

1. Introduction

Bone health is fundamental to overall physical function, as bones provide structural support, protect vital organs, and enable mobility. Maintaining strong and healthy bones depends critically on the balance between bone resorption and bone formation.^1–3 Low bone mineral density (BMD) leads to significant disability, increased dependency, diminished quality of life, and higher economic burdens on healthcare systems.^3–5 The World Health Organization (WHO) recognizes reduced bone density and mass as a major public health concern, particularly among older adults and postmenopausal women.^1,3 Identified risk factors include age, female sex, family history, low body weight, sedentary lifestyle, smoking, and excessive alcohol consumption.^3,4 Medications, bone diseases, and insufficient physical activity also adversely affect bone health. Previous studies have further indicated that hormone levels, immune cells, and gastrointestinal functions play roles in maintaining bone balance.^6,7

The gastrointestinal tract absorbs bone-relevant minerals (calcium, magnesium, phosphorus) and produces endocrine factors (incretin, serotonin) that signal to bone cells, yet the precise mechanisms in humans remain unclear, with most evidence from animal or in vitro models.^7–9 Gut microbiota (GM) is thought to influence bone health through nutrient absorption, vitamin synthesis, and modulation of inflammation.^10–13 However, the direction of this relationship is uncertain: GM changes could drive bone loss, or conversely, osteoporosis-related shifts may alter GM composition.^3,5,8 Dietary interventions are frequently promoted for osteoporosis, but high-quality evidence is limited by recall bias and few fracture endpoints; whether diet alone can reverse bone loss in established osteoporosis remains an open question.^14,15

Recent systematic reviews and controlled trials indicate that probiotics and synbiotics play a crucial role in maintaining a healthy GM and enhancing overall well-being. Probiotics are described as live microorganisms that grant health benefits when administered in sufficient amounts.^16,17 On the other hand, synbiotics refer to the synergistic combination of probiotics and prebiotics. Preclinical and small clinical trials suggest that probiotics can enhance the absorption of essential nutrients, such as magnesium and calcium, thereby fortifying the skeletal structure.^16–18 By fostering a balanced GM, these beneficial microorganisms contribute to the reduction of inflammation linked to various chronic conditions that impact both gastrointestinal and bone health. This underscores the interrelationship between digestive health and skeletal integrity, implying that prioritizing the gut microbiome may yield substantial benefits for overall health.^19–21

Studies on the relationship between bone health and probiotics have yielded conflicting results. Several SRs/MAs report modest benefits, while others find null effects, particularly when stratified by age, sex, or intervention duration. For example, Huang et al. (2022) reported that oral probiotic supplementation improved gut microbiota diversity and promoted bone growth and density.⁸ However, the study by Sergeev et al. (2020) reported no significant effects. Their three-month study revealed that probiotic capsules did not affect bone mineral content in individuals with osteoporosis.²²

To date, at least 16 systematic reviews and meta-analyses have examined the effect of probiotics/synbiotics on bone health, with conflicting findings regarding population subgroups (age, sex, menopausal status), intervention duration, and bone sites. An umbrella review is therefore appropriate to synthesize this existing review-level evidence, assess the confidence in reported effects using AMSTAR2, and conduct a meta-analysis with overlap control and subgroup analyses. Considering the rising prevalence of aging-related issues, we aim to investigate skeletal changes in systematic reviews and meta-analyses in response to probiotics and synbiotic supplementation to gain a comprehensive understanding of their impact on bone health as the primary outcome, with muscle outcomes considered only as secondary outcomes.

2. Methods

2.1. Study design

We carried out this umbrella review with a meta-analysis following the Cochrane Handbook for Systematic Reviews of Interventions. The results were reported consistently with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (Supplemental Table 1).²³ This umbrella review identified all systematic reviews and meta-analyses regarding the effect of probiotics and synbiotics supplementation on bone and muscle health. The study protocol is registered in PROSPERO (CRD42025636002).

2.2. Literature search

Two investigators (NL and MM) independently searched the PubMed, Medline, Web of Science, and Cochrane databases from inception to 6 February 2025 to identify meta-analyses and systematic reviews of clinical trials and animal studies. The search strategy was designed accordingly to keywords including “Bone health”, “Osteoporosis”, “Osteopenia”, “Bone Disease”, “Low Bone Density”, “Bone Mineral Density”, bone loss”, “probiotic*”, “synbiotic*”, “Lactobacillus”, and “Bifidobacterium”. Supplemental Table 2 elucidates the search strategy.

All identified publications underwent a three-step parallel review of titles, abstracts, and full texts based on predefined both inclusion and exclusion criteria by two researchers (N.L. and M.M.), with discrepancies resolved by consensus (HS.E.).

2.3. Eligibility criteria

The umbrella review included meta-analyses and systematic reviews that performed quantitative analyses of the effect of probiotics and synbiotics on bone health.

Studies have been screened based on the following PICOS:

1. Population: subjects with or without previous osteoporosis disorders or animal models that had or had not undergone aging-inducing manipulations.

2. Intervention: any probiotics or synbiotics supplementation.

3. Comparators: subjects or animal models matching the population of interest who are given a placebo or a control group without intervention.

4. Outcome: Our primary outcomes were changes in bone parameters. Secondary outcomes included plasma biochemical profile, inflammatory markers, muscle mass, and muscle strength.

5. Type of study: systematic reviews and meta-analyses.

The exclusion criteria:

1. Original articles, letters, editorials, narrative reviews.

2. Studies reported a response to probiotics or synbiotics supplementation without investigating bone and muscle health.

2.4. Data extraction and data synthesis

We extracted baseline characteristics of the studies, including the first author, publication year, country, study design, study groups, and population characteristics, type and duration of intervention, and primary and secondary outcomes, including bone parammeters, plasma biochemical profile, inflammatory markers, muscle mass, and muscle strength. Additionally, we noted protocol registry, risk of bias assessment tools, source of heterogeneity assessment method, and publication bias assessment method.

The extracted studies included two categories of animal and human studies. Only meta-analyses on human studies were included in the meta-analysis, and the rest were examined in the systematic review. The overlap between primary studies across included meta-analyses has been checked. We combined the results of the included meta-analyses, because the percent of overlap was less than 15% among the included meta-analyses. The overlap among the included meta-analyses was assessed using the Corrected Covered Area (CCA) method. The calculated CCA was 3.57%, indicating a slight overlap among the included reviews. Thus, we combined the results of the included meta-analyses.

Regarding the existing heterogeneity among studies, the pooled ES and 95% CI were evaluated using random effects models with a restricted maximum likelihood approach. The effect sizes are weighted mean difference (WMD) in this study. Also, significant heterogeneity between studies was examined using the I² statistic and Cochrane’s Q test, which is indicated by I² values above 50% or Q test p values below 0.1.²⁴ In order to point out the sources of variation, we conducted a subgroup analysis based on the BMD measure point, number of studies, sample size, and the gender of the participants. Sensitivity analysis was also used to determine the impact of excluding a specific study on the overall effect size (WMD).

To evaluate publication bias, we visually inspected funnel plots. However, because fewer than 10 studies were included in each meta-analysis, formal regression-based tests (Begg’s tests) have low power. Instead, we assessed funnel plot asymmetry cautiously. When asymmetry suggestive of a small-study effect was observed, we applied the trim-and-fill method as a sensitivity analysis to estimate the potential impact of unpublished or missing studies on the pooled effect sizes.^25–27P-values below 0.05 specified significance. All analyses were performed using STATA version 17.0 (Stata Inc., College Station, Texas, USA).

2.5. Quality assessment

We assessed the methodological quality of the included systematic reviews using AMSTAR2 (A MeaSurement Tool to Assess Systematic Reviews).²⁸ The AMSTAR2 criteria encompass items related to protocol registration before the commencement of the review (item 2), adequacy of the literature search (item 4), justification for excluding individual studies (item 7), risk of bias from individual studies being included in the review (item 9), appropriateness of meta-analytical methods (item 11), consideration of risk of bias when interpreting the results of the review (item 13), and assessment of the presence and likely impact of publication bias (item 15).

Following AMSTAR2 guidance, we did not calculate a numerical overall score. Instead, two authors (N.L. and M.M.) independently rated each review’s overall confidence as high, moderate, low, or critically low based on critical domain failures (items 2, 4, 7, 9, 11, 13, 15). A review was rated low confidence if it had one or more critical domain failures and critically low confidence if it had multiple critical domain failures. Any disagreement was resolved by the senior author (H.S.E.). Critical-domain failures identified in the included reviews are reported in Supplemental Table 3 (e.g., lack of a registered protocol [item 2], inadequate literature search [item 4], and/or failure to justify study exclusions [item 7]).

3. Results

Our initial search identified 930 articles (488 from PubMed/MEDLINE, 260 from Web of Science, and 182 from Cochrane). After removing duplicates and screening titles and abstracts, we narrowed the selection to 81 articles. We then assessed the full texts, resulting in the inclusion of sixteen systematic reviews and meta-analyses in our umbrella review (Figure 1). Of the 81 full-text articles assessed, 65 were excluded for the following reasons: 29 were primary studies (not systematic reviews/meta-analyses), 18 had no relevant bone or muscle outcomes, 12 were narrative reviews or editorials, 4 did not administer probiotics/synbiotics as the intervention, and 2 had insufficient data for extraction.

Figure 1.

Flow chart of study selection for inclusion studies in the umbrella review.

In this umbrella review, each “included study” is a systematic review or meta-analysis (SR/MA). The narrative synthesis of skeletal parameters, biochemical markers, and inflammatory outcomes (sections 3.3 and 3.4) reports the findings as stated by the included SRs/MAs; we did not re-analyse their primary data (section 3.5). For combining the results of the included meta-analyses, we used WMD when it was possible.

3.1. Characteristics of the included studies

Our umbrella review included seven studies originating from China,^{3,5,7,8,10,12,16} two from Iran,^4,9 two from Canada,^2,11 and one each from India,¹ Indonesia,¹³ Spain,¹⁵ Cyprus,¹⁴ and Dubai.⁶ Three studies focused on probiotics and synbiotics,^4,7,9 while thirteen exclusively examined probiotics.^{1–3,5,6,8,10–16}

Among the 16 included studies, 12 were systematic reviews with meta-analyses (references 1, 3–5, 7, 8, 10–15) and 4 were systematic reviews without meta-analysis (references 2, 6, 9 and 16).

Eleven involved humans,^{2,3,5–8,10,12–15} two included both humans and animals,^4,9 and three studied animals only.^1,11,16 Of the human studies, only one was conducted in children⁸; the remaining 10 involved adults^{2,3,5–7,10,12–15} (Table 1). The number of participants in the meta-analyses varied, with a minimum of 447⁴ and a maximum of 3,245.⁸

Table 1.

General characteristics of included studies that evaluating the effect of probiotic and synbiotic supplementation in bone health.

Author (Year)	Country	Type of study	Databases searched (search date)	Study group and population	Included primary studies	Type and duration of intervention
Yumol J.,et al. (2025)¹¹	Canada	Meta-analysis and systematic review	MEDLINE, Embase, CINAHL Complete, and Web of Science (January 2024)	1028 Rodent models	71 Animal studies	Probiotics (2 weeks to 26 weeks)
Wang Y.,et al. (2025)¹²	China	Meta-analysis and systematic review	PubMed, Embase, Cochrane Library, and Web of Science databases (July 2024)	1028 Elderly	22 Clinical trials	Probiotics (3 weeks to 48 weeks)
Handajani Y.,et al. (2024)¹³	Indonesia	Meta-analysis and systematic review	PubMed, EBSCO, and Proquest, (April 2023)	733 Adults	7 Clinical trials	Probiotics (8 weeks to 12 months)
Bose SH.,et al. (2024)¹	India	Meta-analysis and systematic review	PubMed, Google Scholar and Web of Science, (June 2023)	453 Animal models of postmenopausal osteoporosis	22 Animal studies	Probiotics (4 weeks to 3 months)
Moyseos M.,et al. (2024)¹⁴	Cyprus	Meta-analysis and systematic review	MEDLINE, EMBASE, and Web of Science (January 2024)	311 Elderly	3 Clinical trials	Probiotics (3 weeks to 32 weeks)
Moreno M.,et al. (2024)¹⁵	Spain	Meta-analysis and systematic review	MEDLINE/PubMed, Cochrane Library, SCOPUS databases (June 2023)	1215 Adults	8 Clinical trials	Probiotics (8 weeks to 24 weeks)
Wang F.,et al. (2024)¹⁰	China	Meta-analysis and systematic review	MEDLINE, PubMed, Embase, Web of Science, CNKI (August 2024)	1183 Postmenopausal women	12 Clinical trials	Probiotics (3 to 24 months)
Lashkarbolouk N.,et al. (2024)⁹	Iran	Systematic review	PubMed, Medline, Cochrane, Google Scholar and Web of Science (April 2024)	1086 Animal models and 1888 elderly	20 Clinical trials and 30 animal studies	Probiotics and synbiotics (2 day to 48 weeks)
Billington E.,et al. (2023)²	Canada	Systematic review	EMBASE, MEDLINE, and Cochrane Library (October 2020)	569 Postmenopausal women	6 Clinical trials	Probiotics (6 to 12 months)
Huang Z.,et al. (2022)⁸	China	Meta-analysis and systematic review	PubMed, Web of Science, Embase, Cochrane Library, CINAHL, and CNKI Database (August 2021)	3245 Children	20 Clinical trials, and 8 crossover trials	Probiotics (3 weeks to 12 months)
Li J.,et al. (2021)¹⁶	China	Systematic review	PubMed and Embase (June 2020)	828 Rodent models	30 Animal studies	Probiotics (2 weeks to 12 weeks)
Yu J.,et al. (2021)³	China	Meta-analysis and systematic review	PubMed, EMBASE, and Cochrane Library (November 2020)	497 Postmenopausal women	5 Clinical trials	Probiotics (6 to 12 months)
Malmir H.,et al. (2021)⁴	Iran	Meta-analysis and systematic review	PubMed, Medline, Web of Science, SCOPUS, EMBASE, and Google scholar (December 2020)	3916 Animal models and 437 adults	7 Clinical trials, and 37 animal studies	Probiotics and synbiotics (1day to 12 months)
Zeng L.,et al. (2021)⁵	China	Meta-analysis and systematic review	Web of Science, MEDLINE, VIP Database, Wanfang, PubMed, CBM Database, and CNKI Database (June 2021)	1156 Elderly	10 Clinical trials	Probiotics (6 to 12 months)
Abboud M.,et al. (2020)⁶	United Arab Emirates	Systematic review	PubMed, MEDLINE, CINAHL, EMBASE, and Cochrane Library (November 2020)	473 Adults	7 Clinical trials	Probiotics (6 to 12 weeks)
Liu, Y.,et al. (2019)⁷	China	Meta-analysis and systematic review	Cochrane Library, Embase, PubMed, Web of Science, CINAHL, CNKI Database, and Wanfang Database (January 2019)	564 Middle-aged adults and elderly	6 Clinical trials	Probiotics and synbiotics (6 to 48 weeks)

To assess the risk of bias of the primary studies they included, the systematic reviews and meta-analyses most commonly used the Cochrane Risk of Bias tool (for human randomised controlled trials) and the SYRCLE tool (for animal studies). No included SR/MA performed a de novo risk-of-bias assessment; all reported the results of their own assessments using these tools (Table 2).

Table 2.

Main results and assessment method of included studies that evaluating the effect of probiotic and synbiotic supplementation in bone health.

Author (Year)	Protocol registry	Risk of bias assessment tools	Source of heterogeneity assessment method	Publication bias assessment method	Results of publication bias	Main results	Main conclusion
Yumol J.,et al. (2025)¹¹	PROSPERO (CRD42021250351)	SYRCLE’s tool	Pooled analysis	Visual inspection of Funnel Plots, Egger’s Test, trim, and fill method	No evidence of publication bias was observed by Egger’ test (P <0.05)	In intact rodents, probiotics resulted in greater vBMD (SMD = 0.43, 95% CI [0.13, 0.74], I 2 = 3%, p < 0.05) and higher BV/TV (SMD = 0.63, 95% CI [0.25, 1.02], I 2 = 57%, p < 0.05) at the femur without changes in cortical bone structure. In ovariectomized models, probiotic resulted in greater vBMD (femur: SMD = 1.28, 95% CI [1.01, 1.55], I 2 = 3%, p < 0.05; tibia: SMD = 1.29, 95% CI [0.52, 2.05], I 2 = 67%, p < 0.05; and spine: SMD = 1.47, 95% CI [0.97, 1.97], I 2 = 26%, p < 0.05) as well as higher BV/TV (femur: SMD = 1.16, 95% CI [0.80, 1.52], I 2 = 56%, p < 0.05; tibia: SMD = 2.13, 95% CI [1.09, 3.17], I 2 = 79%, p < 0.05; spine: SMD = 2.04, 95% CI)	Probiotics as a strategy to improve bone outcomes in rodent models.
Wang Y.,et al. (2025)¹²	PROSPERO ( CRD42024571445)	Cochrane Collaboration’s tool	Meta-regression, sensitivity analysis, subgroup analysis	Fixed effect model, Random model, Visual inspection of Funnel Plots, Egger’s Test	No evidence of publication bias was observed by Egger’ test (P = 0.333 > 0.05, P = 0.838 > 0.05)	No statistically significant difference between probiotics and placebo in improving muscle mass and Lean body mass in sarcopenia patients; MD: 0.66, 95%CI: - 0.01–1.33; Z = 1.93, P > 0.05; MD: - 0.13, 95%CI: -0.81–0.55; Z = 0.38, P = 0.71 > 0.05. Probiotics were found to significantly improve overall muscle strength compared with the placebo group. MD: 2.99, 95%CI: 2.14–3.85; Z = 6.86, P < 0.001	Probiotics can significantly improve global muscle strength in patients with sarcopenia
Handajani Y.,et al. (2024)¹³	PROSPERO (CRD42023466881)	Cochrane Collaboration’s tool	Meta-regression	Visual inspection of Funnel Plots, Egger’s Test, trim, and fill method	No evidence of publication bias was observed by Egger’s test (p = 0.38)	Probiotic resulted in a significant increase of muscle mass with adjusted SMD of 0.962 (95% CI: 0.288 to 1.635, p = 0.049) using till and trim analysis and muscle strength with SMD of 1.037 (95% CI: 0.077 to 1.996, p = 0.03)	Probiotic treatment improved the amount of muscle and its endurance
Bose SH.,et al. (2024)¹	PROSPERO (CRD42023445290)	SYRCLE’s tool	Pooled analysis	Visual inspection of Funnel Plots, Egger’s Test, trim, and fill method	Significant publication bias for femur total BMD (P < 0·001), femur trabecular BMD (P < 0·001), vertebral BMD (P < 0·001), BV/TV (femur, tibia and vertebral) (P < 0·001), serum Ca (P < 0·001) and Oc.S/B.S (P = 0·001) founded. The estimates for femur total BMD, vertebral BMD, femur BV/TV, vertebral BV/TV, serum Ca and Oc.S/B.S did not change after using Trim and Fill method. Publication bias was absent for tibia trabecular BMD, tibia cortical BMD, serum osteocalcin, serum CTX-1 and serum ALP.	Probiotic treatment favours an increase in BMD significantly at all the sites, with the highest effect seen in femur total BMD (SMD = 5·24, 95 % CI (3·04, 7·43); P < 0·001). Also, probiotics significantly improve BV/TV, with the most significant effects observed in the tibia and vertebra (SMD of 2·26, 95 % CI (0·75, 3·77); P-value=0·003). We compared the effects of Lactobacillus sp. and Bifidobacterium sp. on osteoporotic bone, and both improved BMD and BV/TV, but Lactobacillus sp. had a larger effect size	Probiotics have the potential to improve bone health and prevent postmenopausal osteoporosis
Moyseos M.,et al. (2024)¹⁴	No previous protocol registry	Cochrane Collaboration’s tool	Meta-regression, sensitivity analysis	Random model, Visual inspection of Funnel Plots	No evidence of publication bias was observed by the funnel plot asymmetry test	A significant reduction in symptoms across all outcomes measured (self-reported pain, impediment, and serum hs-CRP) was evident with Lactobacillus casei Shirota (SMD: −2.26 [95% CI −4.87, 0.34]; z-value 1.70; p-value 0.09)	Probiotics of the Lactobacillus strains might be of use for managing pain and inflammation in osteoarthritis
Moreno M. et al. (2024)¹⁵	PROSPERO (CRD42022360514)	Cochrane Collaboration’s tool	Meta-regression, sensitivity analysis, subgroup analysis	Fixed effect model, Random model, Visual inspection of Funnel Plots, Egger’s Test	Egger test results revealed publication bias for muscle strength ((P =0.062), and no publication bias for gait speed (P=0.603)	Probiotic were effective in increasing muscle strength by handgrip strength (mean difference [MD], 2.50 kg [95% CI, 1.33-3.66]; P < .0001) and physical performance and function by gait speed (MD, 0.10 m/s [95% CI, 1.33-3.66]; P < .0001) and physical performance and function by gait speed (MD, 0.10 m/s [95%CI, 0.03-0.16]; P ¼ .003), but when sensitivity analysis was applied, the effectiveness was only maintained for gait speed	Probiotic supplementation seem to improve muscle strength and physical function
Wang F.,et al. (2024)¹⁰	PROSPERO (CRD42024576764)	Cochrane Collaboration’s tool	Meta-regression, sensitivity analysis, subgroup analysis	Visual inspection of Funnel Plots, Egger’s Test, trim, and fill method	Egger test results revealed publication bias for the effects of probiotic supplementation on hip BMD (t=2.42, P=0.042), while the results regarding lumbar spine BMD did not show publication bias (t=1.52, p=0.162). The trim-and-fill method did not show significant changes (z=2.945, P=0.003)	Probiotic supplementation showed significantly greater BMD in both the lumbar spine (SMD= 0.60, 95% confidence interval [CI] 0.14 to 1.05) and the hip (SMD = 0.74, 95%CI 0.15 to 1.33). Additionally, probiotic supplementation was associated with reduced levels of CTX (SMD = -1.51, 95%CI -1.88 to -0.41) and BALP (SMD = -1.80, 95%CI -2.78 to -0.81). Subgroup analyses revealed that the increase in BMD due to probiotic supplementation was more significant in postmenopausal women with osteopenia than in those with osteoporosis	Supplementation with probiotics may increase BMD among postmenopausal women, with stronger evidence in women with osteopenia than osteoporosis
Lashkarbolouk N.,et al. (2024)⁹	PROSPERO (CRD42023448422)	Cochrane Collaboration’s and SYRCLE’s tool	No assessment	No assessment	No assessment	Most of human and animal studies reported an improvement in physical performance, a decrease in frailty index, and a lower reduction in BMD in the intervention groups. Body composition tends to increase in muscle ratio, muscle mass, and reduce in apendicular lean mass and muscle atrophy. Also, the intervention induced bone turnover and mineral absorption, significantly increasing Ca, P, and Mg absorption and short chain fatty acids concentration. Inflammatory markers, including IL1, IL6, IL17, T helper 17, and TNF-α decreased; while, an increase in IL10 and IFN-γ was reported	Prebiotics, probiotics, or synbiotics supplementations could effectively improve the physical performance and muscle strength, and reduce the risk of bone loss and frailty in the elderly
Billington E.,et al. (2023)²	PROSPERO (CRD42019134208)	Cochrane Collaboration’s tool	No assessment	No assessment	No assessment	Four studies examined Lactobacillus-containing probiotics, one assessed a proprietary blend of lactic acid bacteria, and one evaluated Bacillus subtilis. Five studies reported on changes in BMD at the lumbar spine with three demonstrating no difference between probiotic and control groups. Two studies reported improvement in lumbar spine BMD in the probiotic group. Change in hip BMD was reported in four studies, with three demonstrating no difference and one reported an increase in hip BMD	Effects of probiotic interventions on BMD were inconsistent, with the majority of studies demonstrating no benefit at the spine or hip. Probiotic effects on bone turnover markers were similarly heterogeneous
Huang Z.,et al. (2022)⁸	PROSPERO (CRD42021282606)	Cochrane Collaboration’s tool	Meta-regression, subgroup analysis	Begg’s tests	No evidence of publication bias was observed by Begg’s test (z = − 0.34, Pr>\|z\| = 1.00)	Significant differences were found in BMD (SMD 0.473; 95% CI, 0.281 to 0.665; p < 0.001; I 2 = 0.00%) and total serum Ca (SMD 1.069; 95% CI, 0.395 to 1.744; p < 0.001; I 2 = 61.9%). A significant difference was reported in height Z score for age (SMD = 0.112; 95% CI, 0.003 to 0.222; P = 0.044; I 2 = 0%)	Intestinal flora intervention was an effec tive method of improving bone mineral density, serum calcium, and height in infants, children, and adolescents
Li J.,et al. (2021)¹⁶	No previous protocol registry	N.A.	No assessment	No assessment	No assessment	Most studies reported increased BMD and a significant decrease of bone volume fraction (BV/TV) after using probiotics	Probiotics were found to reverse the GM dysbiosis and rescue bone loss
Yu J.,et al. (2021)³	No previous protocol registry	Cochrane Collaboration’s too	Meta-regression, sensitivity analysis, subgroup analysis	Visual inspection of Funnel Plots, Egger’s Test, Begg’s tests	Funnel plot was symmetrical and excluded publication bias for spine BMD (Begg’s test zc =0.73, p=0.462; Egger’s test t=−0.22, p=0.843), and hip BMD (Begg’s test zc =−0.24, p=1.00; Egger’s test t=1.59, p=0.209)	Probiotic supplements were associated with a significantly higher BMD in the lumbar spine (SMD=0.27, 95%CI 0.09 to 0.44). There was no difference between probiotic supplements and BMD in hips (SMD=0.22, 95%CI −0.07 to 0.52). CTX-1 levels in the treatment groups were significantly lower (SMD=−0.34, 95%CI −0.60 to −0.09). Levels of BALP, OC.OPG, and TNF-α did not differ between the probiotic and placebo groups	Supplementation with probiotics could increase lumbar BMD
Malmir H.,et al. (2021)⁴	No previous protocol registry	Cochrane Collaboration’s tool	Meta-regression, sensitivity analysis, subgroup analysis	Visual inspection of Funnel Plots, Egger’s Test, Begg’s tests	Funnel plots indicated moderate asymmetry, suggesting that publication bias cannot be completely excluded as a factor of influence on the present meta-analysis. Begg’s and Egger’s regression tests provided no evidence of substantial publication bias	Probiotic consumption affects bone health parameters such as serum Ca (WMD: 3.82 mmol/l; 95% CI: 1.05, 6.59 mmol/l; I-square=98.0%, P < 0.0001) and PTH (WMD: −5.53 ng/l; 95%CI: −9.83, −0.86 ng/l, I-square=98.2%, P < 0.0001). Spinal and total hip BMD was not affected significantly by probiotic consumption (WMD: 1.45 g/cm2; 95% CI: −0.38, 3.28 g/cm2). In most studies, Lactobacillus species such as L. helveticus, L. reuteri, and L. casei were consumed. Some strains of Bifidobacterium and Lactobacillus including L. reuteri, L. casei, L. paracasei, L. bulgaricus, and L. acidophilus have indicated beneficial effects on bone health parameters	Probiotic supplementation might improve bone health
Zeng L.,et al. (2021)⁵	PROSPERO (CRD42020085934)	Cochrane Collaboration’s tool	Meta-regression, subgroup analysis	Random effect model	No assessment	Total hip’s BMD was not statistically significant, while the lumbar spine’s BMD was significant higher (SMD 1.16 (0.21, 2.12), P=0.02, random effect model). CTX in the experimental group was lower (SMD −0.83 (−1.50, −0.16), P=0.02, random effect model). Compared with control group, the adverse events in the experimental group were not statistically significant	Probiotics may be safety supplements to improve the lumbar spine’s BMD of patients with osteoporosis and osteopenia
Abboud M.,et al. (2020)⁶	OSF registry	Cochrane Collaboration’s tool	No assessment	No assessment	No assessment	Comparators were placebo, vitamin D, lower vitamin D dose, and probiotics and lower vitamin D dose. The co-supplementation yielded greater health benefits than its comparators did in all studies except in one assessing IBS. Beneficial effects included decreased disease severity, improved mental health, metabolic parameters, mainly insulin sensitivity, dyslipidemia, inflammation, and antioxidative capacity, and lower use of healthcare	Co-supplementation of vitamin D and probiotics generated greater health benefits than its comparators did
Liu, Y.,et al. (2019)⁷	No previous protocol registry	Cochrane Collaboration’s tool	Meta-regression, sensitivity analysis	Visual inspection of Funnel Plots	Funnel plots indicated moderate asymmetry, suggesting that publication bias cannot be completely excluded as a factor of influence on the present meta-analysis	Probiotics, prebiotics, or synbiotics supplementation was able to significantly elevate serum Ca levels (0.52 mg/dl, 95% CI [0.38, 0.66], heterogeneity: p = .13, I 2 = 44%), while the results of metaanalysis failed to support the effects of this supplementation on the parameters related to bone health, including BMD, parathyroid hormone, osteocalcin, and alkaline phosphatase (−0.04 g/cm2, 95% CI [−0.16, 0.04], heterogeneity: p = .47, I 2 = 0%)	Probiotics, prebiotics, or synbiotics supplementation exerts a facilitating influence on the level of serum calcium, while the present study has not yet supported the beneficial effects of such interventions on bone health

Bone volume fractions: BV/TV, Bone marrow density: BMD, Irritable bowel syndrome: IBS, Parathyroid hormone: PTH, Tumour necrosis factor: TNF-α, Interleukin: IL, Interferon: IFN-γ, Collagen type 1 cross-linked C-telopeptide: CTX-1, Bone-specific alkaline phosphatase: BALP, Osteoprotegerin: OPG, Osteocalcin: OC, Calcium: Ca, Weighted mean difference: WMD, Standardized mean difference: SMD.

Supplemental Table 3 shows the overlap between primary studies across included meta-analyses in our umbrella review with a meta-analysis.

3.2. Type, dosage, and duration of probiotics and synbiotics

All studies in this umbrella review used an average probiotic dose of at least 10⁸ CFU/g (colony-forming units per gram), which meets the current standard for effective probiotics necessary for measurable health benefits. They typically report a range of 10⁸ to 10¹¹ CFU, with a concentration of 10⁸ CFU/g often cited as necessary for a clinical effect due to the challenges of surviving the stomach’s acidity.^1,2,13

Probiotics administration methods varied in animal studies, including fermented products, dietary supplements, and oral gavage. All human studies tried oral supplements or consumed them in the diet as a component of fermented dairy products (e.g., cheese, yogurt, kefir).^3–5 Animal studies in this systematic review tied oral gavage to their trials. The chosen method can significantly affect probiotics’ efficacy by influencing beneficial microbes’ viability and colonization potential.^6–8,14

The synbiotics in these studies included bacterial strains along with cheese, yogurt, kefir, isoflavone, calcium, vitamin D3, fructose, galactooligosaccharides, soluble corn fibers, and vitamin K. These components were chosen for their synergistic effects to enhance gut microbiota diversity and overall health.^4,9

Treatment durations in animal studies and clinical trials varied from 1 day to 48 weeks. However, most studies used 6 to 12 weeks for intervention duration and suggested that 6 to 12 weeks is often necessary to observe significant effects on bone health in various studies. Billington E’s study suggests that the variability in BMD results and bone turnover markers may stem from the necessity for all studies to last at least six months to capture maximal changes in these markers.²

Most studies focused on Lactobacillus (L) and Bifidobacterium (B) strains as probiotics, with some also using Bacillus. The most common probiotics studied were L. reuteri, L. casei, L. paracasei, L. plantarum, L. acidophilus, L. helveticus, L. rhamnosus, B. bifidum, B. longum, B. breve, B. infantis, Bacillus subtilis, and Streptococcus thermophilus.^1–16 These strains were often evaluated for their ability to survive the digestive tract, adhere to intestinal mucosa, and produce beneficial metabolites like short-chain fatty acids. Lactobacillus species, such as L. reuteri, L. paracasei, and L. plantarum, are well-studied for maintaining balanced gut microbiota, while Bifidobacterium strains like B. bifidum, B. lactis, and B. longum are linked to dietary fiber fermentation and beneficial short-chain fatty acid production.^4,9,16 Additionally, Bacillus strains, such as Bacillus coagulans, have gained interest for their spore-forming ability, allowing them to survive harsh gastrointestinal conditions and reach the intestines intact. Together, these microorganisms enhance gut microbiome diversity and promote gut health.^5–7,15

3.3. Skeletal parameters

All included studies examined the effects of probiotics and synbiotics on BMD. BMD and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry or single-photon absorptiometry. Three systematic reviews found that probiotics and synbiotics significantly increased BMD along with enhanced bone mineral content (BMC) at various sites, including the femur, tibia, hip, and vertebra.^6,9,16 In contrast, one systematic review investigated BMD changes, reporting no differences between probiotic and control groups.²

Eight meta-analyses studies focused on hip and lumbar spine BMD, with four showing a significant impact of probiotics and synbiotics on hip BMD,^1,8,10,11 while four did not.^3–5,7 In contrast, five studies indicated a significant effect on lumbar BMD,^1,3,5,8,10 with three showing no significant impact.^4,7 Malmir’s study revealed that probiotics consumption had no effect on spinal BMD or total hip BMD.⁴ In Bose’s study, probiotics treatment was found to significantly increase BMD across all sites (total femur, trabecular femur, trabecular tibia, cortical tibia, and vertebra), with the greatest effect noted in total femoral BMD (SMD = 5·24, 95 % CI (3·04, 7·43); P < 0·001).¹ A meta-analysis of rodent studies indicated that probiotics significantly improved femoral and hip BMD (SMD = 0.43, 95% CI [0.13, 0.74], I² = 3%, p = 0.006), which correlated with increased BV/TV (SMD = 0.63, 95% CI [0.25, 1.02], I² = 57%, p = 0.001). No significant effects were observed on BV/TV and BMD at the spine (SMD = 0.68, 95% CI [−0.31, 1.67], I² = 83%, p = 0.18), (SMD = 0.42, 95% CI [−0.01, 0.84], I² = 61%, p = 0.05).¹¹

Two meta-analyses indicate that probiotics supplementation significantly improves muscle mass, muscle strength, and handgrip strength in older adults compared to controls.^13,15 For instance, Handajani Y et al., (2024), reported significant improvements in muscle mass (SMD = 0.684, 95% CI: 0.002-1.366, p = 0.049), muscle strength (SMD = 1.037, 95% CI: 0.077-1.996, p = 0.03), gait speed (MD [95% CI], 0.10 m/s [0.03-0.16], P = .003; I 2 = 0%) and handgrip strength (MD = 2.50 kg, 95% CI: 1.33-3.66, p < .001, I² = 0%) with probiotics use.¹³ A meta-analysis in sarcopenic patients found no significant difference between probiotics and placebo in muscle mass, handgrip strength, or lean body mass, but did show a significant improvement in global muscle strength with probiotics (MD: 2.99, 95%CI: 2.14–3.85; Z = 6.86, P < 0.001).¹² Similarly, a meta-analysis in osteoarthritis (OA) patients reported that probiotics had no effect on WOMAC scores, including pain, stiffness, or physical function.¹⁴

Additionally, one meta-analysis mentioned that probiotics treatment enhanced bone volume compared to controls, showing notable improvements in bone volume fractions (BV/TV) in ovariectomized animals, particularly in the tibia and vertebra (SMD=2·26, 95 % CI of (0·75, 3·77), P-value=0·003). Also, reported a reduction in bone formation rate (BFR) upon probiotics treatment; however, the effect was not statistically significant (SMD = −0·66, CI (–1·34, 0·02); P = 0·056). On osteoclast surface/bone surface (Oc.S/B.S) data, it was reported that although probiotics treatment tended to reduce Oc. S/B.S, the effect was not statistically significant.¹

Three systematic reviews on human and animal models declared that probiotics feeding also affected an increase in trabecular thickness, bone volume, tibia length, and femur weight, and a significant reduction in trabecular separation. However, no meta-analysis was done on these bone parameters.^4,6,9

3.4. Plasma biochemical profile and inflammatory markers

Nine studies reported osteocalcin (OC) levels in intervention and control groups. Results indicated that probiotics and synbiotics treatments tended to increase this bone formation marker significantly. However, six of these articles conducted meta-analyses that found this change was not statistically significant. For example, Zeng’s study found no statistically significant improvement in OC between the experimental and control groups (SMD −0.12 (−0.85, 0.61), P=0.75, random effects model).⁵

Nine studies examined serum Collagen cross-linked C-telopeptide (CTX) levels in intervention and control groups, indicating that probiotics and synbiotic treatments may reduce bone resorption by lowering CTX levels. Four meta-analyses were performed; three found a significant decrease in CTX, while Bose’s meta-analysis noted that probiotics treatment modestly lowered serum CTX-1, though the effect was not significant. Yu’s study indicated that probiotics supplements lowered CTX levels compared to the placebo group (SMD = −0.34, 95% CI −0.60 to −0.09), with substantial heterogeneity.¹

Nine studies reported a decrease in serum bone-specific alkaline phosphatase (BALP), but a meta-analysis revealed no significant relationship in three of these studies. Liu’s research indicated no significant differences in BALP levels among participants receiving probiotics, prebiotics, or synbiotics compared to the control group (-−10.64 U/L, 95% CI [−43.67, 22.38], heterogeneity: p = .0010, I² = 86%). In sensitivity analyses, excluding individual articles showed no significant difference between experimental and control groups (6.94 U/L, 95% CI [−3.97, 17.85], p = .63), (−24.52 U/L, 95% CI [−86.96, 37.92], p = .0004; 22.22 U/L, 95% CI [−90.91, 46.48], p = .0006).⁷ The study by Wang mentioned that probiotics supplementation was associated with reduced levels of BALP (SMD = -1.80, 95%CI -2.78 to -0.81).¹⁰

Three studies on the Receptor activator of nuclear factor-kB ligand (RANKL) produced mixed results: one reported significant improvement,⁹ while the others found no statistically significant changes.^5,10

One systematic review assessed additional resorption markers such as urinary type I collagen cross-linked N-telopeptide (NTX) and type 1 procollagen N-terminal propeptide (P1NP); one study in this systematic review observed a reduction in NTX and an increase in P1NP with probiotics, while the other two found no difference.² Also, one meta-analysis of P1NP reported that probiotics did not show any significant alteration.¹⁰

Four studies examined osteoprotegerin (OPG). One systematic review found a significant improvement in this marker, while three meta-analyses reported no association between probiotics and OPG. The study by Zeng indicated that the improvement in OPG in the experimental group was not statistically significant compared to the control group (WMD −0.10 (−1.00, 0.79), P = 0.82, random effects model).⁵

Six studies examined serum and urinary calcium levels, revealing that both probiotics and synbiotics increased serum calcium compared to controls, though one meta-analysis found non-significant results.¹ Three other meta-analyses reported increased serum calcium levels and absorption. Malmir’s study indicated that probiotics consumption significantly raised serum calcium levels (weighted mean difference: 3.82 mmol/l; 95% CI: 1.05, 6.59 mmol/l; I-square = 98.0%, P < 0.001) and notably affected urinary calcium levels (WMD: 4.85 mmol/l; 95% CI: 1.16, 8.53 mmol/l; I-square = 97.6%, P < 0.001).⁴

Five studies reported parathyroid hormone (PTH) levels with no change (two studies) or a decrease in levels (three studies). Three studies meta-analysed PTH levels; one showed significant decreases,⁴ while two reported insignificant changes.^7,8 Liu’s analysis found no significant difference in PTH levels between participants receiving probiotics, prebiotics, or synbiotics and the control group (0.71 pg/ml, 95% CI [−7.46, 8.88], heterogeneity: p = .09, I² = 59%). Conversely, the Malmir study indicated that probiotics consumption significantly reduced PTH levels (WMD: −5.53 ng/l; 95% CI: −9.83, −0.86 ng/l, I² = 98.2%, P < 0.001).⁴

Four studies declared the positive effects of probiotics on tumor necrosis factor-α (TNF-α). One meta-analysis reported no evidence that probiotics supplements were associated with decreased levels of TNF-α.³

Four studies investigated vitamin D status, while three focused on phosphorus and magnesium. All reported that probiotics and synbiotics elevated these markers, but none performed a meta-analysis on these levels.

Two systematic reviews highlighted significant changes in plasma biochemical profiles, including zonulin, claudin-3, branched-chain amino acids, creatine kinase, butyrylcarnitine, N-terminal telopeptide, tartrate-resistant acid phosphatase, and short-chain fatty acids. It noted a reduction in inflammatory markers such as CRP, IL-1, IL-6, IL-8, and interferon-γ.⁹ Additionally, another systematic review reported a significant decrease in specific inflammatory markers like IL-1 and antioxidative parameters.⁶

3.5. Results of meta–analysis

3.5.1. The effect of probiotics supplementation on BMD

Combining the results of five meta-analyses comprising 10 effect sizes (WMD) indicated that probiotic supplementation significantly increased the BMD levels (WMD= 0.39 (95% CI: 0.14, 0.63), p = 0.002) (Figure 2). There was a high amount of heterogeneity (I²=71.5%, p <0.001) among the studies. After excluding each study using sensitivity analysis, no significant difference in the pooled results was found (Sup Figure 1). Begg’s tests (p = 0.788) indicated there was no minor study effect. Visual inspection of the funnel plot, however, revealed an asymmetry to the right of the funnel plot. Therefore, the trim-and-fill method was applied by 10 meta-analyses (five imputed by test), and the effects of probiotics on BMD levels became statistically non-significant after a minor decrease in ES magnitude (WMD: 0.232 (95% CI: -0.018, 0.481)). The subgroup analysis results indicated that probiotic supplementation had a positive effect on spine BMD (p 0.002). Also, a greater positive effect on BMD was observed in studies that included only females (p <0.001). Similarly, a greater positive effect on BMD was seen in studies with a sample size of ≥ 150 and a number of studies of ≥ 5 (Table 3). These exploratory findings should be interpreted with caution and require confirmation in future studies designed a priori to test subgroup effects.

Figure 2.

(a) Forest plot detailing effect sizes and 95% confidence intervals (CIs) and (b) funnel plot of the effect of probiotics supplementation on BMD.

Table 3.

Subgroup analyses for the effect of probiotics on BMD.

	Effect size (n	ES (95% CI)^a	P-within^b	I² (%)^c	P-heterogeneity^d
BMD measure point
hip	5	0.31 (-0.05, 0.67)	0.094	70.1%	0.010
spine	5	0.46 (0.17, 0.74)	0.002	26.5%	0.245
Gender
m/f	4	0.42 (-0.32, 1.15)	0.270	56.0%	0.078
f	6	0.39 (0.19, 0.60)	0.000	30.8%	0.204
Sample Size
< 150	4	0.42 (-0.29, 1.13)	0.243	55.0%	0.083
≥ 150	6	0.40 (0.19, 0.61)	0.000	32.0%	0.196
Study Number
< 5	6	0.59 (-0.03, 1.21)	0.061	62.3%	0.021
≥ 5	4	0.34 (0.15, 0.53)	0.000	29.8%	0.234

Abbreviations: BMD, Bone Mineral Density; m, male; f, female; CI, Confidence interval; ES, Effect size.

^aObtained from the random-effects model.

^bRefers to the mean (95% CI).

^cInconsistency, percentage of variation across studies due to heterogeneity.

^dObtained from the Q-test.

3.5.2. The effect of probiotic supplementation on muscle strength

The pooled estimate of three meta-analyses of clinical trials reported a significant effect of probiotic supplementation on improving MS of participants (WMD = 1.99 (95% CI: 0.42, 3.57), p = 0.013) (Figure 3). The heterogeneity test results (I² = 87.0%, p = <0.001) revealed that there was high heterogeneity among meta-analyses. The overall effects of probiotic intervention on MS became nonsignificant following the removal of wang et al. (WMD = 1.466, 95%CI: -.502, 3.435) and Besora-Menore et al. (WMD = 1.749, 95%CI: -.700, 4.199) using sensitivity analysis (Sup Figure 2). Based on the Begg test results (p = 0.602), no significant publication bias was observed.

Figure 3.

(a) Forest plot detailing effect sizes and 95% confidence intervals (CIs) and (b) funnel plot of the effect of probiotics supplementation on MS.

3.5.3. The effect of probiotic supplementation on muscle mass

Two meta-analyses evaluated the effects of probiotic supplementation on MM. The pooled results from these studies indicated that MM was significantly enhanced after probiotic supplementation (WMD = 0.46, 95% CI 0.23, 0.68), p = <0.001 (Figure 4). The heterogeneity test results (I²= 0.0%, p = 0.740) revealed that there was probably low heterogeneity among studies.

Figure 4.

Forest plot detailing effect sizes and 95% confidence intervals (CIs) of the effect of probiotics supplementation on MM.

3.6. Quality assessment of the included studies

The methodological quality of the 16 included systematic reviews was assessed using the AMSTAR2 tool. Following official guidance, we did not calculate a numerical overall score. Instead, two reviewers independently assigned each review an overall confidence rating of high, moderate, low, or critically low based on failures in seven critical domains (items 2, 4, 7, 9, 11, 13, and 15).

Overall confidence ratings: High confidence – 11 reviews,^{1,3,4,7,8,10–15} Moderate confidence – 1 review,⁵ Low confidence – 4 reviews,^2,6,9,16 Critically low confidence – 0 reviews.

Thus, 11 reviews were rated as high confidence, 1 as moderate confidence, and 4 as low confidences. These counts are consistent across the Abstract, Results, and Table 4.

Table 4.

Results of assessment of the methodological quality of included meta-analysis.

Author (Year)	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Q12	Q13	Q14	Q15	Q16
Yumol J.,et al. (2025)¹¹	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Wang Y.,et al. (2025)¹²	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Handajani Y.,et al. (2024)¹³	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Bose SH.,et al. (2024)¹	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Moyseos M.,et al. (2024)¹⁴	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Moreno M. et al. (2024)¹⁵	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Wang F.,et al. (2024)¹⁰	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Lashkarbolouk N.,et al. (2024)⁹	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Partial Yes	Yes	No	No	Yes	Yes	No	Yes
Billington E.,et al. (2023)²	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Partial Yes	Yes	No	No	Yes	Yes	No	Yes
Huang Z.,et al. (2022)⁸	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Li J.,et al. (2021)¹⁶	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Partial Yes	Yes	No	No	Yes	Yes	No	Yes
Yu J.,et al. (2021)³	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Malmir H.,et al. (2021)⁴	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Zeng L.,et al. (2021)⁵	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Abboud M.,et al. (2020)⁶	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Partial Yes	Yes	No	No	Yes	Yes	No	Yes
Liu, Y.,et al. (2019)⁷	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes

Most common critical-domain failures among moderate- and low-confidence reviews:

1. Item 11 (appropriateness of meta-analytic methods) – rated “No” in 4 reviews,^2,6,9,16 all of which were systematic reviews without a quantitative synthesis or with inappropriate pooling.

2. Item 15 (assessment of publication bias) – rated “No” in 5 reviews.^2,5,6,9,16

3. Item 9 (adequacy of risk-of-bias assessment) – rated “Partial Yes” in 4 reviews,^2,6,9,16 indicating that a risk-of-bias tool was used but applied incompletely or not reported in sufficient detail.

No review failed the other critical domains (items 2, 4, 7, 13), meaning that all 16 reviews had a registered protocol (or justified its absence), performed an adequate literature search, justified study exclusions, and considered risk of bias when interpreting results.

4. Discussion

Osteoporosis and osteopenia primarily affect older adults, reducing their resilience to physical stress. As the global population ages, the rising prevalence of osteoporosis presents significant challenges. Bone density loss increases fracture risk, leads to prolonged disability, increases the health costs, and diminishes quality of life.^3,5,8 Probiotics and synbiotics have been proposed as potential adjunctive interventions, but the strength and consistency of the supporting evidence require careful scrutiny. Dysbiosis may increase intestinal permeability, promoting the translocation of pro-inflammatory cytokines that can harm bone tissue. GM is involved in vitamin synthesis, lipid metabolism, and immune regulation.^11–13 Animal studies show that metabolites such as short-chain fatty acids (SCFAs), particularly butyrate, can influence osteoblast and osteoclast activity.^29–31 However, these mechanistic data come mainly from rodent models or in vitro experiments. Their translation into clinical benefits in humans remains incompletely established.

In this umbrella meta-analysis of human studies, probiotic supplementation significantly increased BMD in the pooled analysis (ES = 0.39 [0.14–0.63], p = 0.002). Nevertheless, this finding must be interpreted with substantial caution for several reasons. First, visual inspection of the funnel plot showed asymmetry, and after trim-and-fill correction (imputing five missing studies), the effect size became non-significant (ES = 0.23 [0.018–0.481]). Second, there is high heterogeneity: I² = 71.5% (p < 0.001), indicating that the true effect varies considerably across studies and settings; heterogeneity was only partially explained by BMD measurement site, sample size, and participant sex. Third, positive effects were more consistently observed at the lumbar spine (five meta-analyses showing significant effects) than at the hip (four meta-analyses positive, four null), suggesting that probiotics, if effective, may preferentially influence trabecular-rich sites. Fourth, the pooled effect on muscle strength (ES = 1.99 [0.42–3.57], p = 0.013) became non-significant after its removal in sensitivity analyses (Supplemental Figure 2), indicating that the result is not robust to the exclusion of a single study. Thus, the overall human evidence for probiotics improving BMD or muscle strength is suggestive but not robust. It does not support strong clinical recommendations or claims of causality (Figure 5).

Figure 5.

Graphical abstracts of the study.

4.1 Type, dosage, and duration of supplementation (human studies)

Most included studies used Lactobacillus and Bifidobacterium strains at doses of 10⁸–10¹¹ CFU/g. The minimum dose of 10⁸ CFU/g is commonly cited as necessary to survive gastric transit, but direct dose-response evidence for bone outcomes is lacking.^15,16,32 Intervention durations varied from 6 to 48 weeks. While some systematic reviews suggested that longer durations (≥6 months) are associated with more positive BMD changes,^2,3,9 this observation is based on cross-study comparisons, not within-trial randomization.

4.2 Musculoskeletal parameters: Inconsistent across skeletal sites

Our synthesis shows that probiotics and synbiotics may have a modest positive effect on lumbar spine BMD in some meta-analyses^1,3,5,8,10 but not in other sites.^4,7 Hip BMD effects are even less consistent, with as many null as positive meta-analyses. This discrepancy may reflect differences in bone composition (trabecular vs. cortical), turnover rates, or mechanical loading. At present, the evidence does not support a claim that probiotics improve BMD at all skeletal sites. Pooled estimates showed significant improvements in muscle mass (ES = 0.46 [0.23–0.68], I² = 0%) and strength (ES = 1.99 [0.42–3.57], I² = 87%). However, the high heterogeneity for strength and its sensitivity to single-study exclusion limit confidence. Moreover, a meta-analysis in sarcopenic patients found no significant difference in muscle mass or handgrip strength, although global muscle strength improved.¹² In osteoarthritis patients, probiotics had no effect on physical function.¹⁴ Collectively, the evidence for muscle outcomes is mixed and not robust.

4.3. Plasma biochemical profile and inflammatory markers

Despite plausible mechanisms, most bone turnover markers did not show statistically significant meta-analytic changes (osteocalcin, BALP, OPG and RANKL). Two meta-analyses showed no significant change in PTH level^7,8; one showed a significant reduction, but with very high heterogeneity (I² = 98.2%).⁴ Three out of four meta-analyses showed a significant decrease in CTX, but heterogeneity was substantial.^1,3,10 Calcium levels were increased in most meta-analyses, but this may be confounded by the calcium content of fermented dairy products used as delivery vehicles.^5–9 Inflammatory markers (TNF-α, CRP, IL-6) showed some reductions, but not uniformly across studies. The lack of consistent effects on bone turnover markers, despite occasional BMD changes, raises questions about the clinical meaningfulness of the BMD findings. It is possible that the small BMD effect size (ES = 0.39) is below the detection threshold of these markers, or that the markers were measured at inappropriate time points.

Why effects may be absent or inconsistent: slow bone remodeling is one factor, as most trials lasted only 6–12 weeks whereas measurable BMD changes typically require at least six months,² meaning short-term studies are unlikely to capture true effects. Regarding the target population, probiotics may only benefit individuals with low baseline BMD, inadequate calcium or vitamin D intake, or known gut dysbiosis, while studies enrolling healthy, replete populations may show ceiling effects. Concomitant medications are also relevant because many older adults take calcium, vitamin D, bisphosphonates, or other drugs that could obscure or interact with probiotic effects. Biomarker variability plays a role: bone turnover markers have high biological variability (diurnal, dietary, assay-dependent), and single time-point measurements in small samples may fail to detect true but small changes.^33–37 Strain specificity matters because not all probiotic strains are equally effective; most studies used Lactobacillus and Bifidobacterium, but within these genera effects may differ, yet no head-to-head strain comparisons exist for bone outcomes. High heterogeneity (I² often >70%) was present for BMD and muscle strength, and this heterogeneity is not merely a statistical nuisance – it reflects genuine variation in study populations, interventions, comparator groups, outcome measurements, and follow-up durations. Consequently, any pooled estimate must be viewed as an average that may not apply to any specific clinical setting. Subgroup analyses (e.g., by BMD site, sample size, gender) were exploratory and not pre-specified in most original meta-analyses; they should be interpreted as hypothesis-generating, not confirmatory.^32,38–41 For example, the observation that Asian studies showed a larger effect than European studies¹² was based on post-hoc comparisons with high subgroup heterogeneity (I² = 76%). This could reflect differences in diet, baseline calcium intake, or probiotic strains, but it may also be a spurious finding, and we refrain from interpreting it as a true geographical effect. In addition to the limitations noted above (heterogeneity, publication bias, fragility of results), the following limitations warrant emphasis: although low (Supplemental Table 3), some degree of overlap across included meta-analyses cannot be ruled out, which may introduce bias through double-counting of original trials. We did not apply GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) to individual outcomes; doing so would likely rate the evidence as low or very low for most outcomes due to high heterogeneity, imprecision, and publication bias. There is an inability to adjust for multiple comparisons, as subgroup analyses and multiple outcome testing increase the risk of type I errors, so our conclusions should be viewed as exploratory. Finally, the lack of individual patient data meant we could not assess effect modification by age, sex, baseline BMD, or probiotic strain at the individual level. In summary, the available human evidence suggests modest, inconsistent, and fragile benefits of probiotics and synbiotics on bone mineral density (primarily lumbar spine) and muscle strength, but these effects are not robust to correction for publication bias or sensitivity analyses. Bone turnover markers and hip BMD show no consistent improvements. Mechanistic plausibility is supported by animal studies, but translation to clinical efficacy remains unproven.^42–47 Current evidence does not support routine prescription of probiotics or synbiotics for the prevention or treatment of osteoporosis or sarcopenia.^48–50 They may be considered as part of a broader dietary approach (e.g., fermented dairy intake), but should not replace established therapies (calcium, vitamin D, bisphosphonates, exercise). Large, well-designed, long-duration (≥12 months) randomized controlled trials are needed, with pre-specified subgroup analyses, standardized probiotic strains and doses, and fracture as a primary endpoint. Mechanistic studies should measure gut microbiota composition and turnover markers longitudinally.

It should be noted that, because the number of contributing meta-analyses/effect sizes was limited, formal assessments of funnel plot asymmetry and small-study effects were considered exploratory and interpreted cautiously. Begg’s test has limited statistical power in analyses with few studies, and funnel plot asymmetry should not be interpreted as definitive evidence of publication bias. In addition, the trim-and-fill procedure was used only as a sensitivity analysis to evaluate the potential influence of potentially missing studies on pooled estimates.

Also,we have avoided strong or definitive conclusions regarding muscle outcomes, and instead state that these findings should be interpreted with great caution and require confirmation in future larger meta-analyses.

5. Conclusion

This umbrella review found that probiotic and synbiotic supplementation was associated with modest, statistically significant benefits for BMD in human studies, although substantial heterogeneity and a trim-and-fill sensitivity analysis that rendered the pooled effect non-significant indicate low to moderate certainty in this estimate. Muscle mass and strength outcomes were derived from very few meta-analyses, with high heterogeneity and sensitivity analyses that eliminated statistical significance; these findings should therefore be considered exploratory and preliminary. Animal studies provide mechanistic plausibility (e.g., modulation of gut microbiota, inflammation, and mineral absorption) but cannot be generalized to human clinical efficacy. The evidence is further limited by overlap among primary studies across the included systematic reviews, variation in methodological quality (AMSTAR2 confidence ratings: 11 high, 5 moderate/low), and the absence of long-term fracture outcomes. Future research should prioritize large, long-term randomized controlled trials with fracture endpoints, standardized probiotic strains and doses, and clear separation of probiotic-only from synbiotic interventions (the latter of which may contain calcium, vitamin D, or prebiotics that independently affect bone). Until such evidence emerges, clinical recommendations remain unsupported.

Supplemental material

Supplemental material - The impact of probiotics and synbiotics supplementation on bone health; an umbrella review of systematic reviews and meta-analysis

Supplemental material for The impact of probiotics and synbiotics supplementation on bone health; an umbrella review of systematic reviews and meta-analysis by Mahdi Mazandarani, Narges Lashkarbolouk, Hanieh-Sadat Ejtahed, Azadeh Dehghani, Roghayeh Molani-Gol, Shirin Hasani-Ranjbar and Bagher Larijani in Sage Open Medicine.

Supplemental material

Supplemental material - The impact of probiotics and synbiotics supplementation on bone health; an umbrella review of systematic reviews and meta-analysis

Supplemental material

Supplemental material - The impact of probiotics and synbiotics supplementation on bone health; an umbrella review of systematic reviews and meta-analysis

Supplemental material

Supplemental material - The impact of probiotics and synbiotics supplementation on bone health; an umbrella review of systematic reviews and meta-analysis

Footnotes

ORCID iD

Mahdi Mazandarani

Ethical considerations

This article does not contain any studies with human participants or animals performed by any of the authors.

Author Contributions

M.M, N.L and H-SE came up with the idea for this article and did the final proofreading. MM, NL, and H-SE undertook the study search and evaluated the articles. NL and MM wrote the manuscript and the tables. A.D, RM did the meta-analysis. SHR and BL supervised the process. All authors contributed to the article and approved the submitted version.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

All data generated or analysed during this study are included in supplementary information files.*

Supplemental material

Supplemental material for this article is available online.

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